WO1997030992A1 - Inhibitors of farnesyl protein transferase - Google Patents

Inhibitors of farnesyl protein transferase Download PDF

Info

Publication number
WO1997030992A1
WO1997030992A1 PCT/US1997/002920 US9702920W WO9730992A1 WO 1997030992 A1 WO1997030992 A1 WO 1997030992A1 US 9702920 W US9702920 W US 9702920W WO 9730992 A1 WO9730992 A1 WO 9730992A1
Authority
WO
WIPO (PCT)
Prior art keywords
imidazol
tetrahydro
benzodiazepine
ylmethyl
phenyl
Prior art date
Application number
PCT/US1997/002920
Other languages
French (fr)
Inventor
Charles Z. Ding
John T. Hunt
Soong-Hoon Kim
Toomis Mitt
Rajeev Bhide
Katerina Leftheris
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26683350&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1997030992(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA002239187A priority Critical patent/CA2239187C/en
Priority to UA98084564A priority patent/UA52642C2/en
Priority to IL12419797A priority patent/IL124197A/en
Priority to JP53039597A priority patent/JP4115529B2/en
Priority to EP97906761A priority patent/EP0892797A4/en
Priority to AU21366/97A priority patent/AU718676B2/en
Priority to NZ330287A priority patent/NZ330287A/en
Priority to SK1173-98A priority patent/SK286568B6/en
Priority to BR9707614A priority patent/BR9707614A/en
Priority to PL328868A priority patent/PL191502B1/en
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to IL14190897A priority patent/IL141908A/en
Priority to RO98-01326A priority patent/RO121118B1/en
Priority to EE9800262A priority patent/EE04309B1/en
Publication of WO1997030992A1 publication Critical patent/WO1997030992A1/en
Priority to LVP-98-129A priority patent/LV12150B/en
Priority to NO19983892A priority patent/NO319395B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to compounds that inhibit farnesyl-protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents.
  • the compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme famesyl protein transferase.
  • the compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
  • the mammalian ras gene family comprises three genes, H-ras, K- ras and N-ras.
  • the ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and differentiation. Overproduction of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.
  • the transforming activity of ras is dependent on localization of the protein to plasma membranes. This membrane binding occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and mandatory step in this sequence of events is the farnesylation of these proteins.
  • the reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as the farnesyl group donor in this reaction.
  • FPT farnesyl protein transferase
  • FPP farnesyl pyrophosphate
  • the ras C-terminus contains a sequence motif termed a "Cys-Aaa ⁇ -Aaa2-Xaa" box (CAAX box), wherein Cys is cysteine,
  • Aaa is an aliphatic amino acid
  • Xaa is a serine or methionine.
  • Farnesylation occurs on the cysteinyl residue of the CAAX box (cys-186), thereby attaching the prenyl group on the protein via a thio-ether linkage.
  • V, W and X are selected from the group consisting of oxygen, hydrogen, R 1 , R 2 or R 3 ;
  • Z and Y are selected from the group consisting of CHR , S0 2 , S0 3 , CO, C ⁇ 2, O, NR 10 , S0 2 NR 1 1 , CONR 12 ,
  • R I 16 R I17 R I 18 R I 19 — S/— / — ⁇ /— / or Z may be absent;
  • R ⁇ 22 , R rt24 , R rt25 , R rt26 , R ⁇ 27 , R ⁇ 28 , R rt29 , R rt30 , R ⁇ 31 , R ⁇ 32 , R ⁇ 33 , R rt 34 , R rt35 , R rt36 , R , and R 38 are selected from the group consisting of hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl;
  • R , R 5 are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R 23 ;
  • U is selected from the group consisting of sulfur, oxygen, NR 24 , CO, SO, S0 2 , C0 2 , NR 25 C0 2 , NR 26 CONR 27 , NR 28 S0 2 , NR 29 S0 2 NR 30 ,
  • R , R , and R 3 are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g.
  • R° and R 23 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo; Any two of R ' , R , and R 3 can be joined to form a cycloalkyl group; R, S and T are selected from the group consisting of CH 2 , CO and
  • A, B, C and D are carbon, oxygen, sulfur or nitrogen. with the provisos that 1. When m is zero then V and W are not both oxygen or
  • W and X together can be oxygen only if Z is either absent, O, NR 10 , o
  • CHR 9 , R 14 R 15 in formulas I and II, and V and X together can be oxygen only if Y is O, NR 10 , o
  • R 23 may be hydrogen except when U is SO, S0 2 , NR 5 C0 2 or
  • R 8 may be hydrogen except when Z is S0 2 , C0 2 , or
  • alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
  • lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
  • substituted alkyl refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, aikylthio, arylthio, aralkylthio, cycloalky
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
  • aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
  • substituted aryl refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, aikylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like.
  • the substituent may be further substituted by halo
  • alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
  • substituted alkenyl refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, aikylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g.
  • alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
  • substituted alkynyl refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, aikylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g.
  • a substituent such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, aikylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano
  • cycloalkyl refers to a optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl.
  • substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom- containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1 , 2 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrroUdinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl
  • bicyclic hetrocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1 - b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazo
  • heteroatoms such as, epoxides and aziridines.
  • heteroatoms shall include oxygen, sulfur and nitrogen.
  • the "ABC” ring and the “ABCD” fused ring to the diazepine ring may be monocyclic or bicyclic, e.g. napthyl or quinolyl in nature.
  • the compounds of formulas l-IV may form salts which are also within the scope of this invention.
  • Pharmaceutically acceptable (i.e. non- toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
  • the compounds of formulas l-IV may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
  • alkali metals such as sodium, potassium and lithium
  • alkaline earth metals such as calcium and magnesium
  • organic bases such as dicyclohexylamine, tributylamine, pyridine
  • amino acids such as arginine, lysine and the like.
  • Such salts may be obtained, for example, by exchanging the carboxyiic acid protons, if they contain a carboxyiic acid, in compounds l-IV with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
  • Other salts can be formed as known to those skilled in the art.
  • the compounds for formulas l-IV may form salts with a variety of organic and inorganic acids.
  • Such salts include those formed with hydrogen chloride, hydroxy methane sulfonic acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like).
  • Such salts may be formed by reacting compounds l-IV in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
  • zwitterions inner salts
  • Compounds of the formulas l-IV may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formulas l-IV) is a prodrug within the scope and spirit of the invention.
  • compounds of the formulas l-IV may be a carboxylate ester moiety.
  • the carboxylate ester may be conveniently formed by esterifying any of the carboxyiic acid functionalities found on the disclosed ring structure(s).
  • prodrug derivatives are well known in the art.
  • prodrug derivatives see:
  • solvates e.g., hydrates
  • Methods of solvation are generally known in the art.
  • the compounds of formulas l-IV are inhibitors of S-famesyl protein transferase. They are thus useful in the treatment of a variety of cancers, including (but not limited to) the following; carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, ovary, prostate, testes, pancreas, esophagus, stomach, gall bladder, cervix, thyroid and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphobiastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promye
  • the compounds of formulas l-IV are especially useful in treatment of tumors having a high incidence of ras involvement, such as colon, lung, and pancreatic tumors and in tumors in which a prenyl transferase contributes to tumor maintenance, tumor growth or tumor development.
  • a composition having one (or a combination) of the compounds of this invention development of tumors in a mammalian host is reduced, or tumor burden is reduced, or tumor regression is produced.
  • Compounds of formulas l-IV may also inhibit tumor angiogenesis, thereby affecting the growth of tumors.
  • Such anti-angiogenesis properties of the compounds of formulas l-IV may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • Compounds of formulas l-IV may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through ras, e.g., neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, polycystic kidney disease and endotoxic shock.
  • Compounds l-IV may be useful as anti-fungal agents.
  • Compounds of formula l-IV may induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases.
  • Compounds of formula l-IV, as modulators of apoptosis will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostrate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,
  • Compounds of formulas l-IV may also be useful in the treatment of diseases associated with farnesyl transferase substrates other than ras (e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21 , phosphorylase kinase, Rap2, RhoB, RhoE, PRL1) that are also post- translationally modified by the enzyme famesyl protein transferase.
  • ras e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21 , phosphorylase kinase, Rap2, RhoB, RhoE, PRL1
  • Compounds of formulas l-IV may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase I and II), and thus be effective in the treatment of diseases associated with other prenyl modifications (e.g., geranylgeranylation) of proteins (e.g. the rap, rab, rac and rho gene products and the like).
  • prenyl transferases e.g., geranylgeranyl transferase I and II
  • proteins e.g. the rap, rab, rac and rho gene products and the like.
  • HDV Hepatitis delta virus
  • the compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formulas l-IV may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate.
  • the compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous, intraperitoneal, subcutaneous, intraabdominal, intramuscular, rectal, vaginal or topical administration. Oral administration may involve the use of slow release formulations, such as biodegradable polymers or prodrugs.
  • the pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration.
  • the compounds can be administered in the form of tablets, capsules, granules, powders and the like.
  • the compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
  • Z 1 CO, S0 2 , C0 2l CONR 5 , S0 3 , S0 2 NR 5 , C(NCN)NR 5
  • the first step is accomplished by the reaction of the anthranilic acid with a phosgene equivalent, such as, phosgene or triphosgene in a mixed aqueous/organic solvent at room temperature to 50°C range.
  • a phosgene equivalent such as, phosgene or triphosgene in a mixed aqueous/organic solvent at room temperature to 50°C range.
  • Step 2 of Scheme 1 may be performed in 2 steps, wherein the isatoic anhydride is condensed with an amino acid in an organic solvent solvent such as pyridine at from 0°C to reflux and the resulting anthraniloylamino acid is cyclized under standard amide bond forming conditions, e.g., using HOBt/carbodiimide in an organic solvent such as DMF at from 0°C to room temperature.
  • is aryl or heteroaryl can be prepared from the compound 3 wherein Ri is bromo, iodo or trifluoromethanesulfonyloxy by a palladium coupling of an aryl or heteroaryl metaloid derivative such as phenylboronic acid in a mixed aqueous/organic solvent, e.g. THF/DMF/water, in the presence of a base, e.g.
  • an aryl metaloid derivative such as phenylboronic acid or tributyl-stannylpyridine
  • a deoxygenated organic e.g., THF
  • a palladium catalyst such as tetrakis(triphenylphosphine) palladium at from room temperature to 100°C.
  • Ri or R2 contain functional groups, e.g., CO2R, which are reduced by, e.g. lithium aluminum hydride, to, e.g. CH2OH, these groups will also be reduced by step 3.
  • the product is acylated or sulfonylated under standard conditions at from -78 C to room temperature (e.g., by reaction with an acid halide R3COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/dichloroethane; by reaction with an O-phenyl ester in an inert organic solvent, e.g. acetonitrile; by reaction with a carboxyiic acid in the presence of a coupling agent, e.g.
  • DCC or EDC in an inert organic solvent such as DMF
  • a haloformate such as ethyl, isopropyl or 4- nitrophenylchloroformate in an inert solvent such as dichloromethane at from 0°C to room temperature in the presence of an optional base such as diisopropylethylamine to form carbamates, some of which, e.g. 4- nitrophenyl-carbamate, are reacted with an amine, e.g.
  • N,N,N'- trimethylethylenediamine at from room temperature to 110°C to form ureas; by reaction with a carboxyiic or sulfonyl anhydride such as succinic anhydride or trifluoromethanesulfonyl anhydride in an inert solvent such as ethyl acetate, dichloromethane or pyridine at from 0°C to room temperature in the presence of an optional base such as diisopropylethylamine; by reaction with an isocyanate in an inert solvent such as THF; by reaction with a carbamyl chloride R5R6NCOX wherein X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine/dimethyl-aminopyridine; by reaction with a sulfonyl halide R3SO2X wherein X is Cl or Br in a mixed aqueous/organ
  • the compound 5 wherein Ri is halogen e.g. bromine
  • Ri halogen
  • a halogenating agent e.g. tetrabutylammonium perbromide
  • the acylation may be performed in such a manner as to obtain the diamide ester; the ester may then be cleaved, e.g., by sodium methoxide in methanol and the resulting alcohol oxidized to an acid, e.g., by Jones reagent; the N1 amide may then be cleaved, e.g., by KOH in aqueous methanol at reflux, and the acid may be coupled with amines under standard peptide coupling conditions to form compounds 5 of Scheme 1 where R or R2 is a carboxamide.
  • R or R2 contain CH2 ⁇ -Prot
  • the protecting group may be removed, e.g., Boc by treatment with an acid such as TFA in an inert solvent such as dichloromethane to form a compound 5 or 6 where Ri or R2 is CH2OH.
  • the compound 5 where Ri or R2 is aryloxyalkyl is prepared from a compound 5 where Ri or R2 is CH2OH by transformation of the alcohol into a leaving group such as a trifiate. e.g., by treatment with triflic anhydride in dichloromethane at -40°C, and displacement with an aralkoxide salt, e.g., in dichloromethane at from -40°C to room temperature.
  • the compound 5 where R or R2 is CH2NH2 is prepared from a compound 5 where R or R2 is CH2OH by transformation of the alcohol into a leaving group such as a trifiate. e.g., by treatment with triflic anhydride in dichloromethane at -40°C, and displacement with ammonia, e.g., in dichloromethane at from -40°C to room temperature.
  • the amine may be subsequently coupled to carboxyiic acids by standard amide bond coupling conditions.
  • the compound 5 is sulfonylated with a beta-haloalkylsulfonyl halide
  • the halide may then be eliminated by a base such as diisopropylethylamine and then nucleophiles such as dimethylamine or sodium imidazolate may be added to the resulting unsaturated sulfonamide by treatment in an organic solvent such as THF or dichloromethane at from room temperature to reflux.
  • an organic solvent such as THF or dichloromethane
  • nucleophiles e.g., by amines such as dimethylamine or N- methylpiperazine in an inert solvent such as THF or DMF in the presence of an optional base such as diisopropylethylamine at from 0°C to 110°C.
  • an acid e.g. acetic acid
  • a reducing agent e.g. NaBH(OAc)3
  • an inert organic solvent e.g. dichloroethane at about room temperature.
  • Reductive alkylation may also be performed using hydrogen and a catalyst such as Pd on carbon in a solvent such as ethanol in the presence of an acid such as acetic acid at about room temperature.
  • the compound of Scheme 1 in which the imidazole contains a 2-dimethylaminomethyl group can be prepared by standard Mannich conditions.
  • HOalkyl by Mitsunobu reaction with the aryl alcohol.
  • the product can be further acylated, sulfonylated or reductively aminated under standard conditions.
  • compound 1 is suitably protected by, for example, a tertbutoxycarbonyl group.
  • the reaction is carried out in an inert organic solvent e.g. THF at about room temperature.
  • the compound 2 where Ri is an amine may be selectively acylated, e.g., by reaction with isobutylchloroformate in an inert solvent such as methylene chloride in the presence of a base such as diisopropylethylamine at about room temperature.
  • the compound 2 where an Ri is R5CONH and another Ri is Br is prepared from the compound where an R is R5CONH by bromination, e.g.
  • the compound 1 is reacted with a compound of the formula R2COC ⁇ 2Me in the presence of an organic acid e.g. acetic acid, a reducing agent, such as, NaCNBH3 or NaBH(OAc)3 in an inert organic solvent, such as, dichloroethane at about room temperature.
  • the intermediate is thereafter deprotected by reaction with, for example, trifluoroacetic acid in an inert organic solvent, e.g. CH2CI2 at about room temperature, and cyclized by heating, e.g., at 60°C to form the compound 2.
  • the compound 2 undergoes reductive alkylation as outlined in Scheme 1 to form a compound 3.
  • the compound 3 may be reduced, e.g. with lithium aluminum hydride, to a compound 4, which may be reacted to form a compound 6 as described in Scheme 12.
  • the compound 2 is reduced to the compound 5, as outlined in Scheme 1 , and the compound 5 is reacted as outlined in Scheme 1.
  • the compound 1 is protected by reaction with, for example, triphenylmethyl chloride or Boc anhydride in an inert organic solvent e.g. acetonitrile or tetrahydrofuran, from about room temperature to reflux. Thereafter the compound 2 is reacted with a compound of the formula R4-L wherein L is a leaving group such as trifiate, in the presence of a base such as diisopropylethylamine in an inert organic solvent such as tetrahydrofuran at from about -78 C to room temperature.
  • R4 may contain a protecting group, e.g., phthalimide, removable by e.g. hydrazine.
  • the reaction of Scheme 5 with R4-L may also be performed on a compound 1 to directly produce a compound 3 without protection/deprotection.
  • a cyanoacetylamino acid is reacted with a dithianediol in a suitable solvent such as ethanol in the presence of bases such as piperidine and triethylamine at from room temperature to 80°C.
  • the intermediate is then cyclized in a suitable solvent such as pyridine in the presence of a catalyst such as pyridinium hydrochloride at an elevated temperature such as 130°C.
  • a catalyst such as pyridinium hydrochloride
  • the compound 1 of Scheme 7 undergoes reduction (e.g., Fe, SnCl2, or TiCl3) under standard conditions.
  • the compound 2 is acylated or sulfonylated under standard conditions (e.g., by reaction with an anhydride and an acylation catalyst such as DMAP, by reaction with an acid halide, by reaction with a carboxyiic acid under standard peptide coupling conditions, by reaction with an alkoxycarbonylchloride, by reaction with an isocyanate, by reaction with a sulfonyl halide or by reaction with a sulfamyl chloride) or reductively alkylated under standard conditions (e.g., by reaction with an aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature).
  • Scheme 8
  • Step 1 of Scheme 8 may be performed in 2 steps, wherein the ethylenediamine is condensed with the halogenated heterocycle either neat or in an organic solvent at elevated temperature and the resulting amino acid is cyclized under standard amide bond forming conditions, e.g., using HOBt/carbodiimide in an organic solvent such as DMF or pyridine at from 0°C to room temperature.
  • Compound 2 of Scheme 8 may itself undergo reductive alkylation with an imidazole containing aldehyde as outlined in Scheme 1 to afford a target compound.
  • Some imidazole aldehydes are prepared as follows. An imidazole containing aldehyde undergoes a Wittig reaction with a compound of the formula triethylphosphonoacetate in the presence of a base, such as, sodium hydride in an inert organic solvent, such as dimethoxyethane, at from about 0°C to room temperature. The product is hydrogenated in an alcohol e.g. ethanol at about room temperature and reduced by reaction with DIBAL in for example dichloroethane at about -78 C.
  • some aminoalkyl containing imidazolylalkanols prepared by known methods (e.g., Buschauer, et. al., Arch. Pharm., 315, 563, (1982)) are protected with a Boc group as in Scheme 3, step 1 , and undergo an oxidation, e.g. under Swern conditions.
  • a monoprotected benzodiazepine such as that described in Scheme 3 is coupled with an optionally protected imidazole-containing carboxyiic acid using standard amide bond formation methods such as isobutylchloroformate in an organic solvent such as THF at from -30°C to room temperature.
  • the resulting amide is reduced with for example borane in an organic solvent such as THF at from room temperature to reflux.
  • a compound 3 of Scheme 12 may contain a nitro group which may be reduced, e.g., by TiCl3, to an amine, which may then be acylated or sulfonylated as described in Scheme 7.
  • step 3 of Scheme 12 the amine protecting group is removed (e.g., Boc by an acid such as TFA in an organic solvent such as methylene chloride).
  • step 4 of Scheme 12 the resulting compound is reacted under standard conditions with a variety of active acylating or sulfonylating agents to form the claimed compound, such as acids under carbodiimide conditions or acid chlorides to form amides; carbonates or chloroformates to form carbamates; carbamyl chlorides or isocyanates to form ureas; sulfonyl chlorides to form sulfonamides; halosulfonates to form sulfamates; sulfamoyl chlorides to form sulfonylureas.
  • active acylating or sulfonylating agents such as acids under carbodiimide conditions or acid chlorides to form amides; carbonates or chloroformates to form carbamates; carbamyl chlorides or isocyanates to
  • step 4 of Scheme 12 the resulting compound is alternatively reacted under standard reductive amination conditions with aldehydes as described in Step 5 of Scheme 1 to form the claimed compounds. If the imidazole is optionally protected, it is then deprotected.
  • a monoprotected benzodiazepine such as that described in Scheme 3 is reductively alkylated with an imidazole- containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature.
  • a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature.
  • the product 2 is attached to a solid support, e.g. polystyrene resin, and the reactions of Scheme 1 may be performed on resin-bound material. Removal from the support, e.g. by treatment with an acid such as trifluoroacetic acid in the presence of a scavenger such as triethylsilane at about room temperature, then provides the compound 6 of Scheme 1.
  • a solid support e.g. polystyrene resin
  • a scavenger such as triethylsilane at about room temperature
  • an aminobenzoic acid is reductively aminated with an N-protected aminoaldehyde under standard conditions, e.g. by reaction with a hydride reagent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride or methanol in the presence of an acid such as acetic acid at from 0°C to about room temperature.
  • a hydride reagent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • a suitable solvent such as methylene chloride or methanol
  • the product is deprotected by, e.g., removal of Boc by treatment with an acid such as TFA or HCl in the presence of an optional scavenger such as dimethylsulfide in a suitable solvent such as methylene chloride or dioxane at about room temperature or removal of Fmoc by treatment with a secondary amine in tetrahydrofuran at about room temperature.
  • an optional scavenger such as dimethylsulfide in a suitable solvent such as methylene chloride or dioxane at about room temperature
  • Fmoc by treatment with a secondary amine in tetrahydrofuran at about room temperature
  • the product is cyclized under standard amide bond forming conditions, such as by treatment with diphenylphosphoryl azide in an organic solvent such as DMF.
  • the product is reacted as described in Scheme 1.
  • step 1 of Scheme 15 a benzodiazepinedione is sulfonylated with chlorosulfonic acid and the resulting sulfonyl chloride is condensed with an amine. Thereafter, the product is reacted as described in Scheme 1.
  • a benzodiazepine of Scheme 1 can be doubly reductively alkylated with an imidazole containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature.
  • a reducing agent such as NaCNBH3 or Na(OAc)3BH
  • organic solvent such as dichloroethane or DMF
  • an acid such as acetic acid at from 0°C to room temperature.
  • a benzodiazepine of Scheme 1 can be reacted with R3-L in an inert solvent such as DMF, THF or methylene chloride in the presence of a base such as diisopropylethylamine or potassium carbonate at from 0°C to 100°C, where L is a leaving group such as chloride, bromide, mesylate, tosylate or trifiate and R3 is a substituted alkyl group, a substituted aryl group or a substituted heterocylic group. Thereafter, the product is reacted as described in Scheme 1.
  • an inert solvent such as DMF, THF or methylene chloride
  • a base such as diisopropylethylamine or potassium carbonate
  • the first step is accomplished by the reaction of a pyridine containing a protected amino group and a methyl group with an oxidizing agent, such as hydrogen peroxide in a suitable solvent such as aqueous acetic acid or trifluoroacetic acid at from room temperature to 75°C.
  • an oxidizing agent such as hydrogen peroxide
  • a suitable solvent such as aqueous acetic acid or trifluoroacetic acid
  • the product is acylated with an acylating agent such as acetic anhydride and rearranged by heating from room temperature to 90°C in a suitable solvent such as acetic acid.
  • the product is deacylated, e.g., with aqueous NaOH at from room temperature to 50°C and oxidized to the aldehyde with e.g. Mn ⁇ 2 in a suitable solvent such as tetrahydrofuran at about room temperature.
  • the product is reductively aminated with an aminoacid ester under standard conditions, e.g., by hydrogenation in an inert solvent such as methanol or by reaction with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
  • an inert solvent such as methanol
  • a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
  • Step 5 The product is deprotected and cyclized with, e.g. treatment with polyphosphoric acid at from room temperature to 100°C.
  • the first step is accomplished by the reaction of a pyrimidine containing a halide and a carboxyiic acid group with an optionally monoprotected diamine in a suitable solvent such as water in the presence of a catalyst such as CuS ⁇ 4 at from room temperature to 100°C. Thereafter, the product is reacted as described in Scheme 14.
  • Scheme 20
  • the first step is accomplished by reductive amination of a nitrobenzaldehyde with an amino acid ester under standard conditions, e.g., by reaction with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
  • a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
  • the nitro group of the product is reduced to an amine under standard conditions, such as reaction with SnCl2 or TiCl3.
  • the product is cyclized by heating with CuCN in an inert solvent such as N-methylpyrrolidinone at from room temperature to 195°C.
  • an inert solvent such as N-methylpyrrolidinone
  • the product is alkylated with an optionally protected imidazolylalkanol under Mitsunobu conditions. Thereafter, the product is optionally reacted as described in Scheme 5.
  • a compound 3 of Scheme 1 may be selectively reduced, e.g. by reaction with a reducing agent, such as borane in an inert organic solvent, such as, tetrahydrofuran at about room temperature. Thereafter, the product (2) is reductively aminated as described in Scheme 1.
  • a reducing agent such as borane in an inert organic solvent, such as, tetrahydrofuran at about room temperature.
  • a compound 4 of Scheme 20 may be first reductively aminated as described in Step 5 of Scheme 1.
  • the optionally esterified ester of the product is hydrolyzed, e.g. by reaction with an alkali hydroxide in a suitable solvent such as aqueous alcohol at from room temperature to reflux.
  • the product is cyclized by standard amide bond forming conditions, e.g. by reaction with BOP in an inert solvent such as DMF in the presence of an optional base such as diisopropylethylamine at about room temperature.
  • a compound 2 of Scheme 12 may be directly deprotected as described in Step 3 of Scheme 12 and reacted as described in Step 4 of Scheme 12.
  • a compound 5 of Scheme 12 may be prepared by reduction, e.g. with lithium aluminum hydride or borane, of a compound 3 of Scheme 23, where Zi does not equal CO.
  • a compound 5 of Scheme 1 may be reacted with an imidazole containing aldehyde and an alkali cyanide such as NaCN in the presence of an acid such as acetic acid in a suitable solvent such as methanol/acetonitrile at about room temperature to form a compound 2.
  • the compound 2 may be reduced, e.g. with lithium aluminum hydride, in a suitable solvent such as ether at about room temperature to form a compound 3.
  • the compound 3 may be reductively aminated under standard conditions to form the compound 4.
  • step 1 of Scheme 25 an N-(2-nitroaryl)-amino acid ester, available by reaction of an amino acid with a 1 -fluoro-2-nitrobenzene followed by esterification, is reduced, e.g. with hydrogen and a palladium catalyst in a suitable solvent such as ethyl acetate at about room temperature.
  • the resulting amine is cyclized to a compound 2 under the reduction conditions.
  • the compound 2 is acylated or sulfonylated as described in Step 4 of Scheme 1.
  • the compound 3 is reduced, e.g. with borane in a suitable solvent such as methanol at about room temperature.
  • the compound 3 wherein Ri is halogen, e.g.
  • a halogenating agent e.g. tetrabutylammonium perbromide
  • an inert solvent such as chloroform
  • step 1 of Scheme 26 the compound 1 is reacted with a methylenating agent such as N,N,N'N'-tetramethyl-diaminomethane in a suitable solvent such as acetic anhydride and DMF at about room temperature. Thereafter, the compound 2 is reacted with a 1 ,2- phenylenediamine in a suitable solvent such as toluene at about 115°C under dehydrating conditions, e.g. with a Dean-Stark trap, in the presence of a hydroquinone. Thereafter, the compound 3 is both reduced and reductively aminated as described in Step 5 of Scheme 1.
  • a methylenating agent such as N,N,N'N'-tetramethyl-diaminomethane in a suitable solvent such as acetic anhydride and DMF at about room temperature.
  • a suitable solvent such as acetic anhydride and DMF
  • the compound 2 is reacted with a 1 ,2- phenylenedi
  • A. 1 ,4-Benzodiazepine-2,5-dione A stirred solution of isatoic anhydride (16.4 g, 0.1 mol) and glycine ethyl ester hydrochloride in 40 mL of pyridine was heated under reflux for 7 h. The resulting suspension was cooled to 0°C for 18 h. The precipitate was collected and washed with ethanol and ether to give Compound A as a light yellow solid.
  • Compound D was prepared from Compound C as described for Compound D of Example 1. Chromatography (silica, 5% methanol, 0.5%ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt provided Example 2 as an off white solid, m.p. 160-162°C. MS: (M+H)+ 383+ Analysis calculated for C24H21N4OCI « 1.85 HCl » 2.5 H2O.
  • Compound C was prepared from Compound B as described for Compound D of Example 1. Chromatography (silica, 10% ethanol/ethyl acetate) provided a clear yellow oil which was converted to the hydrochloride with 4N HCl in dioxane (4mL, rt for 2 hrs) to give Example 3 as an off-white solid. MS: (M+H)+ 289+ Analysis calculated for C23H20N4O # 1.9 HCl.
  • Example 4 D 2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-yl-methyl)-1-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride
  • Example 4 was prepared as a light yellow solid from Compound C as described for Compound D of Example 1. Analysis calculated for C24H22N4O -2.0 HCl » 1.3 H2O.
  • the Boc derivative of Compound A was prepared from 2-amino-N-[(1 ,1- dimethylethoxy)-carbonyl]-phenylmethylamine and methyl pyruvate as described for Compound D of Example 1.
  • the resulting oil was dissolved in a mixture of methylene chloride and TFA (8 mL, 1 :1), the solution was stirred at room temperature for 1 h and concentrated in vacuo.
  • the residue was partitioned between ether and 10% HCl solution and the aqueous solution was made basic with 10N NaOH solution to pH 11 and extracted with ethyl acetate (2 x 50 mL).
  • the combined organic extracts were dried over MgS ⁇ 4 and concentrated to give Compound A as a solid (250 mg, 28%), mp: 149- 151 °C. MS (M+H) 177.
  • Example 5 2,3,4,5-Tetrahydro-1-(1H-imidazol-4-yl-methyl)-2-methyl- 4-(1-naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride
  • Example 5 was prepared as a light yellow solid from Compound C as described for Compound D of Example 1 , mp: 165°C (foams).
  • Example 7 was prepared as a white solid from Compound A as described for Compound D of Example 1 , mp 140 °C (foams). MS (M+H) 419.
  • Example 8 was prepared as a yellow solid from isatoic anhydride and L- methionine methyl ester hydrochloride as described in the following multistep sequence: Compound A of Example 1 ; Compound B of Example 1 , except that ethylene glycol dimethyl ether was used as solvent; Compound C of Example 2; Compound D of Example 1. mp 78-80°C. MS (M+H) 457 Analysis calculated for C27H28N4OS » 1.6 HCl « 2.3 H2O.
  • Example 9 was prepared as a white solid from Compound A as described for Compound D of Example 1 , mp: 145°C (shrinks). MS (M+H) 362 Analysis calculated for C21H23N5O «1.8 HCl » 1.0 H2O.
  • Example 10 was prepared as a white solid from 2- methoxycarbonylbenzenesulfonyl chloride and Compound B of Example 2 as described in the following multistep sequence: Compound C of Example 2; Compound D of Example 1.
  • Compound A was prepared from 6-bromoisatoic anhydride as described for Compound A of Example 1.
  • Example 8 was prepared as a solid from Compound A as described in the following multistep sequence: Compound B of Example 2; Compound C of Example 2; Compound D of Example 1. Chromatography (5% methanol, 0.5%ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion into the hydrochloride salt provided Example 11 , mp 160-162°C. MS (M+H) 461 Analysis calculated for C24H21 BrN4 ⁇ » 1.5 HCl.
  • Example 12 was prepared as a solid from Compound B as described in the following multistep sequence: Compound C of Example 2; Compound D of Example 1. Chromatography (5% methanol, 0.5%ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion into the hydrochloride salt provided Example 12, mp 158-160°C. MS (M+H) 459 Analysis calculated for C30H26N4O » 2.0 HCl -0.58 H2O.
  • Compound C was prepared from Compound B as described for Compound A of Example 6, using methylene chloride as solvent. After aqueous workup, recrystallization from ethyl acetate/hexanes afforded Compound C as a white crystalline solid. MS (M+H)+ 411+.
  • Compound E was prepared from Compound D and Compound C of Example 1 as described for Compound D of Example 1 , with stirring for 16 hours. Chromatography (flash, silica, 9:1 methylene chloride:methanol) afforded (74%) of Compound E as a glass. MS (M+H)+ 653.3.
  • Compound F was prepared from Compound E and Compound C of Example 1 as described for Compound D of Example 1 , with stirring for 16 hours. Chromatography (flash, silica, 9:1 methylene chloride:methanol) afforded (44%) of Compound F as a glass. MS (M+H)+ 700.
  • Example 16 was prepared as a yellow solid from isatoic anhydride and D,L- alanine ethyl ester hydrochloride as described for Example 8, mp 180- 185°C.
  • Example 8 To a suspension of ethylene glycol dimethyl ether (anhydrous, 20 mL) and lithium aluminum hydride (17 mg, 0.45 mmol) under argon at 0° C was slowly added a mixture of Example 8 (75 mg, 0.15 mmol) in ethylene glycol dimethyl ether. The mixture was allowed to warm to room temperature, stirred for 30 min. and heated to reflux (85°C) for 18 hours. The mixture was cooled to 0°C and quenched sequentially with a mixture of tetrahydrofuran and water (1 mL each), aqueous sodium hydroxide, (2 mL, 1 N) and water (1 mL).
  • Example 18 was prepared as a light yellow solid from 8-methyl isatoic anhydride and glycine ethyl ester hydrochloride as described in the following multistep sequence: Compound A of Example 1 , with refluxing for 16 hours; Example 17, except that THF was used as solvent; refluxing with the 4-nitrophenyl ester of 1-naphthoic acid in toluene in the presence of DMAP; Compound D of Example 1. MS (M+H)+ 397 Analysis calculated for C25H24N4O « 2 HCl.
  • Example 19 was prepared from 9-methyl-2,3,4,5-tetrahydro-1 ,4- benzodiazepine as described in the following multistep sequence: Compound A of Example 4; coupling with 1 -naphthoyl chloride using triethylamine in methylene chloride; Boc removal with 4N HCl in dioxane; Compound D of Example 1 ; chromatography (silica, flash, 9/1 CHCI3/CH3OH) followed by treatment with 1M HCl in ether and trituration with ether afford Example 19 as a light yellow solid.. MS (M+H)+ 397
  • Example 21 was prepared as a white solid from chloroacetonitrile and Compound C of Example 1 as described for Example 20, mp 155-160°C. MS (M+H)+ 412 Analysis calculated for C25H25N5O » 3 HCl. Calc'd: C, 57.65; H, 5.42; N, 13.45. Found: C, 57.41 ; H, 5.18; N, 13.17.
  • Iron powder (0.15 g, 2.6 mmol) was added to a solution of Compound F (0.13 g, 0.29 mmol) in 500/50/1 ethanol / water / concentrated HCl (26 ml) at room temperature. The mixture was heated to reflux for 3h, cooled to room temperature, filtered and the filtrate was concentrated under vacuum. The residue was dissolved in CH2CI2 (100 ml), washed with 1 N NaOH (100 ml), and the aqueous layer reextracted with CH2CI2 (2X100 ml). The combined organic extracts were dried (MgS04), filtered and concentrated under vacuum to afford Compound G (0.60 g, 52%) as a solid which was used without further purification.
  • Example 23 The crude material was diluted in methanol (2 mL) and purified by HPLC (YMC S5 ODS 30X250 mm column, solvent A: 10% MeOH/H2 ⁇ w/ 0.1% TFA, solvent B: 90% MeOH/H2 ⁇ w/ 0.1% TFA, gradient: 0-100%B in A over 60 min at a rate of 25 mL ⁇ nin, monitored at 220 nm).
  • the fractions containing the product were combined, concentrated in vacuo, dissolved in 1N HCl and lyophilized, dissolved in water and lyophilized again to give Example 23 as a fluffy white solid (4 mg, 8%).
  • Example 24 was prepared as an amorphous off-white solid from Compound A by the following mulitstep sequence: Compound A of Example 1 , with refluxing for 10 hours; Compound B of Example 2, except that THf was used as solvent and the produc borane complex was decomposed with refluxing aqueous HCl; Compound C of Example 2, except that chromatography was done with 50% ethyl acetate-hexane afforded; Compound D of Example 1 , with the product purified by prep HPLC (YMC S5 ODS (30x250 mm) column, gradient elution from 40 to 100% solvent B (A: 10% methanol:water + 0.1% TFA, B: 10% wate ⁇ methanol + 0.1 % TFA) and converted to the HCl salt by treatment with HCI-MeOH.
  • Example 25 is also Compound F of Example 22.
  • Example 26 16 % aqueous TiCl3 (2 mL) was added to a solution of Example 25 (0.10 g, 0.23 mmol) in AcOH/H2 ⁇ (2 mL, 1 :1). After stirring for 15 min, the reaction was made basic with 1 N NaOH and NaHCO3 and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 CH3OH (9 / 1). The combined organic layers were dried over MgS ⁇ 4, filtered and concentrated to afford 0.92 g. (73 %) of Example 26. A 20 mg. sample of this material was treated with 1 M HCl in ether (2 mL). A light yellow solid was formed which was triturated several times with ether and dried under vacuum to afford Example 26 (23 mg. ) as a light yellow solid. (Example 26 is also Compound G of Example 22.) MS (M+H)+ 398.
  • Benzoyl chloride (0.016 g, 0.013 mL) was added to a solution of Example 26 (0.042 g, 0.10 mmol) in CH2CI2 (1 mL) and triethyl amine (0.01 g, 0.016 mL) at 0°C. After stirring for 2 hr, the mixture was diluted with NaHCO3 (2 mL) and CHCI3 (10 mL). The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgS ⁇ 4, filtered and concentrated. The residue was purified on a silica flash column eluting with CH3CI/CH3OH (9 / 1).
  • Example 27 As a light yellow solid (0.015 g, 28%).
  • Example 28 was prepared from Example 26 and cyclohexanecarbonyl chloride as described for Example 27. The crude product was directly treated with HCl / ether. The yellow solid which formed was triturated with ether several times and dried under vacuum to afford Example 28 as a yellow solid in 90% yield.
  • Example 30 was prepared from Compound A by the following 3 step procedure: Compound A of Example 29; Compound B of Example 29, with refluxing for 4 hours and quenching of excess borane by the dropwise addition of methanol; Compound B of Example 3, with stirring at room temperature for 2 hours and flash chromatography on silica with 10% methanol/chloroform followed by preparative HPLC (YMC S5 ODS (30x250 mm) column; gradient elution from 40 to 100% solvent B (A: 10% methanokwater + 0.1% TFA, B: 10% watermethanol + 0.1% TFA); the clear glassy residue which was converted to the HCl salt by treatment with HCI- MeOH to give Example 30 as a foamy solid.
  • Example 31 was prepared from 7-bromo-1 ,4-benzodiazepine (prepared as described in Compound B of Example 11 ) by the following procedure: Compound A of Example 4; Compound A of Example 29 with stirring for 2 hours and chromatography in ethyl acetate; Compound B of Example 29, with the borane reduction refluxed for 3 hours, the HCl treatment at 60°C for 2 hours, and chromatography with chloroform:methanol:NH4 ⁇ H (90:10:1);
  • Example 33 (0.07 g, 93%) as a white solid.
  • Example 35 was prepared from Compound A as described for Compound D of Example 1. Chromatography (silica, 7% methanol, 0.5%ammonium hydroxide, 93% methylene chloride) followed by conversion to the hydrochloride salt provided Example 35 as a powder, m.p. 97-102°C. MS: (M+H)+ 438+ Analysis calculated for C27H27N5O »1.2 HCl -0.75 H2O 0.25 C4H 1 oO. Calc'd: C, 65.51 ; H, 6.32; N, 13.64; Cl, 8.29. Found: C, 65.55; H, 5.98; N, 13.50; Cl, 8.42.
  • Example 36 was prepared from Compound B using the 2 step procedure of Compound C of Example 2 followed by Compound D of Example 1.
  • Triphenylmethylchloride (6.83 mmol, 1.9 g) was added to a solution of Example 11 (6.83 mmol, 3.15 g) and triethylamine (34 mmol, 4.7 mL) in acetonitrile (100 mL) and the reaction was stirred for 2 hr. The resulting homogeneous yellow solution was concentrated under reduced pressure and purified by flash chromatography to give 3.9 g (81%) of Compound A as a white solid. MS (M+H)+ 703. B.
  • Example 38 was prepared as a green solid in 11% yield from Compound A of Example 37 and 2-(tributylstannyl)furan as described for Compound B of Example 37. MS: (M+H)+ 449+ Example 39
  • Example 39 was prepared as a green solid in 10% yield from Compound A of Example 37 and 2-(tributylstannyl)thiophene as described for Compound B of Example 37. MS: (M+H)+ 465
  • Trifluoroacetic anhydride (0.4 mmol, 60 mL) was added to a solution of 2,3,4,5-tetrahydro-4-(1 -naphthalenylcarbonyl)-7-bromo-1 H-1 ,4- benzodiazepine (prepared as described in Example 1 1 , 0.26 mmol, 100 mg) and NEt3 (1.04 mmol, 150 mL) in CH2CI2 (5 mL) and the homogeneous, colorless solution was maintained at room temperature for 1 hr.
  • Compound B was prepared from Compound A as described for Compound A of Example 6, using methylene chloride as solvent and triethylamine as base. After aqueous workup, recrystallization from ethyl acetate/hexanes afforded Compound B as a white microcrystalline solid. MS (M+H)+ 411+.
  • Example 43 was prepared as an off white solid from Compound B of Example 2 as described for Example 42.
  • Example 44 was prepared as an off white solid from Compound B of Example 12 as described for Example 42. MS (M+H+) 459. 1 H-NMR (CD3OD): 3.40-3.80 (br s, 4H), 4.4(br, 2H), 4.7
  • Example 45 was prepared as an off white solid from Compound B of Example 12 as described for Compound D of Example 1 , using methylene chloride as solvent, 4.3 equivalents of 4-formylimidazole, 4.3 equivalents of sodium triacetoxyborohydride and with stirring for 4 hours. MS (M+H+) 385. 1 H-NMR (CD3OD): 3.5 (br s, 4H), 4.60 (br, 2H), 4.9 (br,
  • Example 47 was prepared as an off white solid from 6-hydroxy- isatoic anhydride by the following procedure: Compound A of Example 1 , with refluxing for 18 hr, and washing of the precipitate with water; formation of the methyl ether by stirring with 1.3 equivalents of methyl iodide in DMF in the presence of K2CO3 at room temperature for 12 hrs; Compound B of
  • Example 1 with quenching with 20% NaOH and water followed by extraction with CH2CI2; Compound C of Example 2, with the product carried on without chromatography; Compound D of Example 1 , using methylene chloride, stirring for 5 hours and purification by flash chromatography (94.5:5:0.5, CH2Cl2:MeOH:NH4 ⁇ H) before formation of the hydrochloride salt.
  • n-Bu ⁇ (2.5 M in THF, 0.22 mL, 0.55 mmol) was added to a solution of Example 11 (0.12 g, 0.26 mmol) in THF (10 mL) at -78°C.
  • the resulting brown solution was stirred for 4 min at -78°C, purged with CO2 for 20 min and quenched with acetic acid/water (2:1 , 2 mL).
  • the solvent was evaporated, the residue was dissolved in methylene chloride, and the solution was washed with brine, dried (Na2SO4) and evaporated.
  • Example 50 (80 mg) as well as a 25% yield of Example 50.
  • TFA (3 mL) was added to the crude alcohol (40 mg) in CH2CI2 (15 mL) at -78°C.
  • the resulting blue solution was treated with solid NaBH4 (0.7 g, 18.5 mmol).
  • the mixture was warmed to room temperature and quenched with NH4OH (10 mL).
  • the solution was diluted with CH2CI2 (20 mL) and washed with aqueous NaOH (1N, 10 mL) and brine (10 mL). Drying over Na2S ⁇ 4 and evaporation of solvent gave a solid which was converted to its HCl salt by lyophilization from 1M HCl to provide Example 49 as a yellow solid (30 mg).
  • Example 49 See Example 49 for the preparation of Example 50.
  • Example 51 was prepared by the following 2 step procedure. Tetrahydro-4-(1 -naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine (prepared as described in Example 12) was reductively alkylated with Compound B of Example 20 as described for Compound D of Example 1 , with stirring for 18 hours. Without workup, the mixture was subjected to flash chromatography (silica, 60 % ethyl acetate-hexanes) to afford the bis-Boc analog. Deprotection and purification as described in Compound C of Example 20 afforded Example 51 as an off-white powder. MS (M+H)+ 502 Analysis calculated for C32H31N5O « 3 HCl -0.5 H2O.
  • Example 52 was prepared from tetrahydro-4-(1- naphthalenylcarbonyl)-7-phenyl-1H-1 ,4-benzodiazepine and [2-(2-[[(1 ,1- dimethyl)-ethoxycarbonyl]amino]methyl)-1-[(1 ,1-dimethyl)-ethoxycarbonyl]- imidazol-4-yl]carboxaldehyde (see Example 21 ) as described for Example
  • Example 53 Sodium triacetoxyborohydride (0.079 g, 0.37 mmol) was added to a solution of Example 26 (0.50 g, 0.12 mmol), benzaldehyde (0.04 g, 0.37 mmol) and AcOH (1 mL) in CH2CI2 (1 mL). After stirring for 16 hr, the reaction was diluted with CH2CI2 (10 mL), NH4OH (3 mL) and NaHCO3 (3 mL), and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over MgS ⁇ 4, filtered and concentrated. The residue was treated with HCI/ether, a yellow solid was formed which was triturated with ether several times and dried under vacuum to afford Example 53 (0.43 g, 60%).
  • Benzenesulphonamide (0.024 g, 0.13 mmol) was added to a solution of Example 26 (0.50 g, 0.12 mmol) and triethylamine (0.019 mL, 0.13mmol) in CH2CI2 (1 mL). After stirring for 16 hr, the reaction was diluted with CHCI3 (10 mL) and NaHCO3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgS ⁇ 4, filtered and concentrated.
  • Example 54 (0.64.2 g, 83 %) as a light brown solid.
  • Example 48 A mixture of Example 48 (50 mg, 0.11 mmol), PyBROP (0.28 g, 0.6 mmol), DMAP (0.04 g, 0.3 mmol) and DIEA (0.3 g, 2.3 mmol) in DMF (5 mL) was stirred for 5 min, aniline (1 mL, 11 mmol) was added and the resulting homogeneous solution was stirred for two days.
  • Example 56 was prepared from m-toluoyl chloride and Example 26 as described for Example 27, with stirring for 16 hr.
  • the HCl salt was formed directly from the crude product to provide a 94% yield of Example 56 as a brown solid.
  • Example 11 A stirred suspension of Example 11 (100 mg, 0.22 mmol), paraformaldehyde (10 mg, 0.33 mmol) and dimethylamine (40% in water, 0.041 mL) in acetic acid was heated at 90°C for 18 h. The mixture was partitioned between ethyl acetate and sat. NaHC ⁇ 3 solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by flash chromatography (30% MeOH, 69% ethyl acetate and 1 % NH4OH) to give a solid which was dissolved in methanol. 1 N HCl in ether was added, and the solvent removed to give Example 59 as a yellow solid (30 mg, 23%). MS (M+H)+ 518
  • Example 26 (0.050 g, 0.12 mmol) was added to a solution of EDC (0.071 , 0.37 mmol), HOAt (0.051 g, 0.37 mmol) and 1-methyl-2- pyrrolecarboxylic acid (0.046 g, 0.37 mmol) in DMF (1 mL). After stirring for 16 hr, the mixture was diluted with CHCI3 (10 mL) and NaHCO3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgS ⁇ 4, filtered and concentrated.
  • Phenyl isocyanate (0.016 mL, 0.15 mmol) was added to a solution of Example 26 (0.050 g, 0.12 mmol) and triethyl amine (0.020 mL, 0.15 mmol) in CH2CI2 (1 mL). After stirring for 16 hr, the reaction was diluted with CHCI3 (10 mL) and NaHC ⁇ 3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgS ⁇ 4, filtered and concentrated. The residue purified on a silica gel eluting with (19/1) CHCI3/CH3OH. The appropriate fractions were concentrated and the residue was treated with HCI/ether. The solid was triturated with ether several times and dried under vacuum to afford Example 66 (0.018 g, 25 %) as a light yellow solid.
  • Example 67 was prepared as a yellow solid in 8% yield from Compound A of Example 37 and 3-(tributylstannyl)pyridine as described for Compound B of Example 37. MS: (M+H)+ 460
  • Example 68 was prepared as a light yellow solid from 8- methoxyisatoic anhydride and glycine ethyl ester hydrochloride as described in the following multistep sequence: Compound A of Example 1 ; Reduction was accomplished by refluxing a solution of the dione with 5 eq of borane- THF in THF for 20 hr; cooling to 0°C, acidifying with 3N HCl, heating at 100°C for 30 min, neutralizing with 5N NaOH followed by extraction with methylene chloride; Compound C of Example 2; Compound D of Example 1. MS (M+H)+ 413 IR: (KBr):- 2926, 2837, 1732, 1630, 1580, 1474, 1252, 1078, 804, 781 cm'l .
  • Example 69 was prepared as a fluffy white solid in 36% overall yield from Compound C as described for Compound C of Example 23 and Compound D of Example 23, with a total of 6 aliquots of aldehyde and hydride necessary to drive the reaction to completion. MS (M+H)+ 460 Analysis calculated for C-29H25N5O » 3 HCl.
  • Example 70 was prepared as a yellow solid from isatoic anhydride and L-methionine-O methyl ester hydrochloride as described in the following sequence: Compound A of Example 1 , with refluxing for 18 hours, evaporation of solvent and partitioning between 1 N hydrochloric acid and dichloromethane; Example 17, except that the free base was carried on; Compound C of Example 2, with flash chromatography on silica eluting with ethyl acetate.hexane (1:2); Compound D of Example 1. mp 145-150°C. MS (M+H)+ 456 Analysis calculated for C27H28N4OS *1.6 H2O » 1.3 HCl.
  • Example 71 was prepared as a yellow solid from isatoic anhydride and D,L-phenylalanine-0 methyl ester hydrochloride as described for Example 70. mp 78-80°C. MS (M+H)+ 473 Analysis calculated for C31 H28N4O » 1.6 H2O « 1.8 HCl.
  • Example 72 was prepared as a white solid from isatoic anhydride and D,L-aspartate-0-dimethyl ester hydrochloride as described for Example 70, except that 5 equivalents of lithium aluminum hydride were used in the reduction step, and the final product was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 155-160°C. MS (M+H)+ 427 Analysis calculated for C26H26N4O2 *1.0 H2O « 1.3 TFA. Calc'd: C, 57.95; H, 4.98; N, 9.45; Cl, 11.25. Found: C, 58.09; H, 4.71 ; N, 9.32; Cl, 11.55.
  • Example 73 was prepared from 2,3,4,5-tetrahydro-3-[2- (methylthio)ethylj-1 H-1 ,4-benzodiazepine (prepared from D, L-methionine-O methyl ester hydrochloride as described in Example 70) by the following procedure: Compound A of Example 4; Compound C of Example 2, carried on without purification; Compound C of Example 4; Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 130-135°C. MS (M+H)+ 456 Analysis calculated for C27H28N4OS » 1.5 H2O » 1.3 TFA.
  • Example 74 was prepared as a white solid from isatoic anhydride and L-phenylalanine-0 methyl ester hydrochloride as described for Example 70, with final purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 152-154°C. MS (M+H)+ 473 Analysis calculated for C31 H28N4O -1.0 H2O « 1.2 TFA. Calc'd: C, 63.94; H, 5.01 N, 8.93; Cl, 10.90. Found: C, 64.12; H, 4.87; N, 8.73; Cl, 11.01.
  • Example 75 was prepared as a white solid from Compound C as described for Compound D of Example 1 , with purification of the final product by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 112°C.
  • Example 76 was prepared as a white solid from 2,3,4,5-tetrahydro-
  • Example 77 was prepared as a white solid from Compound A as described for Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 162-165°C. MS (M+H)+ 440
  • the mixture was extracted with ethyl acetate (2 x 25 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (25 ml, saturated solution) and ammonium chloride (25 mL, sat aqueous solution), dried (Na2SO4), and concentrated in vacuo to a semi-solid.
  • the crude was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and lyophilized to provide the TFA salt of Example 78 as a white solid (330 mg, 83 %), mp 118-120 °C. This material was dissolved in methanol (3 mL) and 1 M HCl (3 mL) was added.
  • Example 78 As a white solid, mp 178-180 °C. MS (M+H)+ 476 Analysis calculated for C21 H23N4 ⁇ 2SBr « 0.25 H2O » 1.2 HCl.
  • Example 79 was prepared as a white solid in 79% yield from Compound A as described for Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 120-123°C. MS (M+H)+ 437 Analysis calculated for C28H28N4O « 1.3 H2O » 1.05 TFA. Calc'd: C, 62.36; H, 5.50 N, 9.66; F, 10.32. Found: C, 62.42; H, 5.17; N, 9.61 ; F, 10.24.
  • Example E was prepared from Compound D as a white solid in 13% yield as described for Compound D of Example 1 , with purification by preparative HPLC (YMC S-5 ODS-A column, 30 X 250 mm; solvent A, 0.1% TFA in 90% water, 10 % methanol; solvent B, 0.1% TFA in 10% water, 90% methanol: 20-100% B in 60 min, flow rate 25 mL/min) and conversion to the HCl salt by adding 1 N HCl to methanol solution of the TFA salt and lyophilizing.
  • preparative HPLC YMC S-5 ODS-A column, 30 X 250 mm
  • solvent A 0.1% TFA in 90% water, 10 % methanol
  • solvent B 0.1% TFA in 10% water, 90% methanol: 20-100% B in 60 min, flow rate 25 mL/min
  • Example 81 was prepared as an offwhite solid from Compound A by the following procedure: Compound C of Example 80; Compound D of Example 80, with stirring for 1 hour and with purification by flash chromatography on silica with ethyl acetate.hexanes (1 :5-1 :1); Compound E of Example 80.
  • Example 82 was prepared from cyclohexylisocyanate as described for Example 66, with column chromatography performed with CHCI3/CH3OH
  • Example 83 was prepared as an offwhite solid from 2,3,4,5- tetrahydro-3-(phenylmethyl)-1 H-naphtho[2,3-e]-1 ,4-diazepine (prepared as described in Example 81) as described in Example 78.
  • Example 85 was prepared as an offwhite solid in 83% yield from
  • Example 86 was prepared as a white solid from D,L-2- naphthylalanine as described for Example 80. MS (M+H)+ 475 1 H-NMR (CD3OD, 400 MHz) d 8.81 (1H, s), 7.84 (4H, m), 7.70 (1H, m), 7.50-
  • Example 87 was prepared as a white solid from D.L-1- naphthylalanine as described for Example 80. MS (M+H)+ 475 1 H-NMR (CD3OD, 400 MHz) d 8.53 (1 H, s), 7.87 (1 H, m), 7.74 (1 H, m), 7.55-
  • Example 88 was prepared as a gray solid in 55% yield from
  • Example 91 was prepared as a light yellow solid from Example 26 and morpholine N-carbonyl chloride as described for Example 27.
  • Example 92 was prepared as a light yellow solid in 67% yield from Example 26 and isobutyryl chloride as described for Example 27, except that the reaction mixture was concentrated after no starting material was observed, the residue was treated with MeOH and 1N NaOH for 30 min, and after workup, the product was treated with HCI/ether.
  • Example 93 was prepared as a pale yellow solid from Compound A as described for Compound D of Example 1. Purification by flash silica gel column chromatography eluting with 9:1 CHCI3: MeOH afforded a solid which was converted to its HCl salt by treatment 1M HCl in ether (95 mg,
  • Example 94 was prepared as a slightly pink powder from N,N- diphenylcarbamyl chloride as described for Example 35, mp >200°C. MS (M+H)+ 500 Analysis calculated for C32H29N5O « 0.4 H2O »1.0 HCl.
  • Example 95 was prepared as an off white solid from methyl chloroformate as described for Example 83.
  • Example 96 was prepared as a white lyophilate in 50% yield from 4-pheny-5-carboxy-1 ,2,3-thiadiazole as described for Example 34, with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA).
  • Example 97 was prepared as a white lyophilate in 6% yield from 2,3-methylenedioxy-benzoic acid as described for Example 34, with purification by preparative HPLC (gradient of aqueous methanol with 0.1%
  • Compound A was prepared from 7-nitroisatoic anhydride and phenylalanine as described for Compound A of Example 1 , except that after refluxing for 1 day, the mixture was concentrated. Dimethyl acetamide was added and the mixture was heated at 150°C for 4 hr, concentrated and water was added. The olive green solid obtained was filtered and air dried to obtain Compound A in 80 % yield). MS (M+H)+ 312
  • Boc anhydride (1.5 g, 7 mmol) was added to a solution of Compound B (2.0 g, 7 mmol) and triethylamine (0.71 g, 7 mmol) in THF (30 mL) under argon. After stirring for 6 hr, the mixture was extracted with CHCI3
  • Example 100 (0.15 g, 89%) as a light yellow solid. MS (M+H)+ 588 Example 100
  • Example 75 in 5 mL of THF at rt and under argon, was added 3 mL (3 mmol) of 1 M borane in THF. A clear, bright yellow solution was obtained on addition. Stirring was continued overnight, after which an additional 2 mL (2 mmol) of 1 M borane in THF was added and stirring was continued an additional 8 hr. After hydrolysis of excess borane by the dropwise addition of methanol, the reaction was evaporated to dryness and the residue dissolved in 0.5 mL each of methanol and cone HCl. The resulting solution was heated at reflux for 2 hr, cooled to rt and evaporated to dryness.
  • Example 100 was prepared as a nearly white solid in 60% yield from Compound A as described for Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and conversion to the HCl salt by treatment with HCI-MeOH. MS (M+H)+ 411
  • each carboxyiic acid to Compound B of Example 33 was carried out using standard HOAt / DIC mediated coupling.
  • the process was automated by using a Hamilton 2200 Liquid Handler.
  • a Zymark Benchmate® robotic workstation was used to carry out the weighings of the test tubes and for purification of the resulting amide products.
  • An IBM PC was used to run the Zymark Benchmate® workstation operating program and to write the Benchmate® procedures.
  • Target compounds were characterized by analytical HPLC and mass spectrometry.

Abstract

This invention relates to compounds that inhibit farnesyl-protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.

Description

INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
Field of the Invention
This invention relates to compounds that inhibit farnesyl-protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme famesyl protein transferase. The compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
Background of the Invention
The mammalian ras gene family comprises three genes, H-ras, K- ras and N-ras. The ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and differentiation. Overproduction of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.
The transforming activity of ras is dependent on localization of the protein to plasma membranes. This membrane binding occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and mandatory step in this sequence of events is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as the farnesyl group donor in this reaction. The ras C-terminus contains a sequence motif termed a "Cys-Aaaι-Aaa2-Xaa" box (CAAX box), wherein Cys is cysteine,
Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (cys-186), thereby attaching the prenyl group on the protein via a thio-ether linkage.
l - Brief Description of the Invention
In accordance with the present invention, compounds of the formulas I, II, III and IV
Figure imgf000004_0001
their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit farnesyl protein transferase which is an enzyme involved in ras oncogene expression. In formulas l-IV and throughout their specification, the above symbols are defined as follows: m, n, r, s and t are 0 or 1 ; p is 0, 1 or 2;
V, W and X are selected from the group consisting of oxygen, hydrogen, R1 , R2 or R3; Z and Y are selected from the group consisting of CHR , S02, S03, CO, Cθ2, O, NR10, S02NR1 1 , CONR12,
N -CN N -CN O
II II II
— C — / — C -N — / — N-C— / — N'SO - / I I I
R13 R14 R15
O
— C -N-N — / -SC-2-N-N — / O NR20 R21 NR22
R I 16RI17 R I 18RI 19 — S/— / — ❖/— / or Z may be absent;
R π6 , π R7 i R π9 , π n10 , R rt1 1 , R rt12 , Rπ13 , R rt14 , R rt15 , R rt16 , Rπ17 , R rt18 , Rπ19 , R π20 , R rt21 ,
R π22 , R rt24 , R rt25 , R rt26 , RΠ27 , RΠ28 , R rt29 , R rt30 , R π31 , Rπ32 , Rπ33 , R rt 34 , R rt35 , R rt36 , R , and R38 are selected from the group consisting of hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl;
R , R5 are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R23;
U is selected from the group consisting of sulfur, oxygen, NR24, CO, SO, S02, C02, NR25C02 , NR26CONR27, NR28S02, NR29S02NR30,
S02NR31 , NR32CO, CONR33, PO^34 and POgR35 or U is absent;
R , R , and R3 are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. CONH2) or substituted carbamyl further selected from CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; R° and R23 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo; Any two of R ' , R , and R3 can be joined to form a cycloalkyl group; R, S and T are selected from the group consisting of CH2, CO and
CH(CH2)pQ wherein Q is NR36R37, OR38, or CN; and
A, B, C and D are carbon, oxygen, sulfur or nitrogen. with the provisos that 1. When m is zero then V and W are not both oxygen or
2. W and X together can be oxygen only if Z is either absent, O, NR10, o
II
— N-C — / or — N-S02- I I
CHR9, R14 R15 in formulas I and II, and V and X together can be oxygen only if Y is O, NR10, o
II
— N-C — / or — N-S02- I I
CHR9, R14 R15 in formulas III and IV or 3. R23 may be hydrogen except when U is SO, S02, NR 5C02 or
NR28S02 , or
4. R8 may be hydrogen except when Z is S02, C02, or
°V\/,NR2° R21NV NR22
R15
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
The expression "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term "substituted alkyl" refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, aikylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. S02NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH2, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyhmidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted. The term "aralkyl" refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term "substituted aryl" refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, aikylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds. The term "substituted alkenyl" refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, aikylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyhmidyl and the like. The term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
The term "substituted alkynyl" refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, aikylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyhmidyl and the like. The term "cycloalkyl" refers to a optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrroUdinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinyl sulfone, 1 ,3-dioxolane and tetrahydro-1 , 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
Exemplary bicyclic hetrocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1 - b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like. Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
Also included are smaller heterocyclos, such as, epoxides and aziridines. The term "heteroatoms" shall include oxygen, sulfur and nitrogen.
The "ABC" ring and the "ABCD" fused ring to the diazepine ring may be monocyclic or bicyclic, e.g. napthyl or quinolyl in nature.
The compounds of formulas l-IV may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non- toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
The compounds of formulas l-IV may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts may be obtained, for example, by exchanging the carboxyiic acid protons, if they contain a carboxyiic acid, in compounds l-IV with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those skilled in the art.
The compounds for formulas l-IV may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydroxy methane sulfonic acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting compounds l-IV in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
In addition, zwitterions ("inner salts") may be formed.
Compounds of the formulas l-IV may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formulas l-IV) is a prodrug within the scope and spirit of the invention.
For example compounds of the formulas l-IV may be a carboxylate ester moiety. The carboxylate ester may be conveniently formed by esterifying any of the carboxyiic acid functionalities found on the disclosed ring structure(s).
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs. edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymoloαy. Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews. 8. 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences. 77, 285 (1988); and e) N. Kakeya, et al., Chem Phar Bull.32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the compounds of formulas l-IV are also with the scope of the present invention. Methods of solvation are generally known in the art. Preferred Moieties
For compounds of the present invention, the following moieties are preferred:
Compounds of Formulas I, II, III and IV wherein m is zero. More preferred are compounds of Formula I, II, III and IV wherein m is zero and n is one.
Most preferred are compounds of formula I wherein m, r, s and t are zero, n is one and "ABCD" is a carbocyclic ring, e.g., benzo.
Use and Utility
The compounds of formulas l-IV are inhibitors of S-famesyl protein transferase. They are thus useful in the treatment of a variety of cancers, including (but not limited to) the following; carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, ovary, prostate, testes, pancreas, esophagus, stomach, gall bladder, cervix, thyroid and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphobiastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; - tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarcoma, and osteosarcoma; other tumors, including melanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma.
The compounds of formulas l-IV are especially useful in treatment of tumors having a high incidence of ras involvement, such as colon, lung, and pancreatic tumors and in tumors in which a prenyl transferase contributes to tumor maintenance, tumor growth or tumor development. By the administration of a composition having one (or a combination) of the compounds of this invention, development of tumors in a mammalian host is reduced, or tumor burden is reduced, or tumor regression is produced. Compounds of formulas l-IV may also inhibit tumor angiogenesis, thereby affecting the growth of tumors. Such anti-angiogenesis properties of the compounds of formulas l-IV may also be useful in the treatment of certain forms of blindness related to retinal vascularization. Compounds of formulas l-IV may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through ras, e.g., neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, polycystic kidney disease and endotoxic shock. Compounds l-IV may be useful as anti-fungal agents.
Compounds of formula l-IV may induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of formula l-IV, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostrate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowl diseases and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.
Compounds of formulas l-IV may also be useful in the treatment of diseases associated with farnesyl transferase substrates other than ras (e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21 , phosphorylase kinase, Rap2, RhoB, RhoE, PRL1) that are also post- translationally modified by the enzyme famesyl protein transferase.
Compounds of formulas l-IV may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase I and II), and thus be effective in the treatment of diseases associated with other prenyl modifications (e.g., geranylgeranylation) of proteins (e.g. the rap, rab, rac and rho gene products and the like). For example, they may find use as drugs against Hepatitis delta virus (HDV) infections, as suggested by the recent finding that geranylgeranylation of the large isoform of the delta antigen of HDV is a requirement for productive viral infection [J. S. Glen, et al.. Science.256. 1331 (1992)].
The compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formulas l-IV may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate.
Farnesyl transferase assays were performed as described in V. Manne et al., Drug Development Research, 34, 121 -137, (1995). The compounds of Examples 1-431 inhibited farnesyl transferase with IC 50 values between 0.1 nM and 100uM. The compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous, intraperitoneal, subcutaneous, intraabdominal, intramuscular, rectal, vaginal or topical administration. Oral administration may involve the use of slow release formulations, such as biodegradable polymers or prodrugs. The pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the like. The compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses. Process of Preparation
Scheme 1
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Z1 = CO, S02, C02l CONR5, S03, S02NR5, C(NCN)NR5
Step 1
The first step is accomplished by the reaction of the anthranilic acid with a phosgene equivalent, such as, phosgene or triphosgene in a mixed aqueous/organic solvent at room temperature to 50°C range.
Step 2
The product is reacted with an amino acid hydrochloride salt or an amino acid ester hydrochloride salt in pyridine at an elevated temperature with reflux as preferred. Step 2 of Scheme 1 may be performed in 2 steps, wherein the isatoic anhydride is condensed with an amino acid in an organic solvent solvent such as pyridine at from 0°C to reflux and the resulting anthraniloylamino acid is cyclized under standard amide bond forming conditions, e.g., using HOBt/carbodiimide in an organic solvent such as DMF at from 0°C to room temperature. Some compounds 1 of Scheme 1 wherein Rl = halogen are not commercially available. Such compounds 3, 4 or 5 of Scheme 1 wherein Ri = halogen can be prepared from compounds 3, 4 or 5 of Scheme 1 wherein Ri = hydrogen by halogenation, for example by reaction with bromine in an organic solvent such as acetic acid at from 0°C to room temperature. The compound 3 wherein R-| is aryl or heteroaryl can be prepared from the compound 3 wherein Ri is bromo, iodo or trifluoromethanesulfonyloxy by a palladium coupling of an aryl or heteroaryl metaloid derivative such as phenylboronic acid in a mixed aqueous/organic solvent, e.g. THF/DMF/water, in the presence of a base, e.g. sodium carbonate, at from room temperature to 90 C. (Alternatively, the compound of Scheme 1 where Ri = aryl or heteroaryl is also prepared from a compound 2 of Scheme 5 where Ri is bromo, iodo or trifluoromethanesulfonyloxy by reaction with an aryl metaloid derivative such as phenylboronic acid or tributyl-stannylpyridine in a deoxygenated organic (e.g., THF) or mixed aqueous/organic solvent system such as aqueous NaHCθ3/toluene in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium at from room temperature to 100°C. Deprotection then affords the target compound.) Alternatively such Suzuki or Stifle couplings can be performed on a compound 1 of Scheme 1 , or on a compound 4 of Scheme 1 , or on a compound 5 of Scheme 1 where the unacylated benzodiazepine nitrogen may be optionally protected, e.g., with a trifluoroacetyl group, and subsequently deprotected. The compound 3 wherein Ri is alkoxy is prepared by alkylation of the corresponding hydroxy compound under standard conditions. The compound 3 wherein Ri is alkylaminoalkylaryl is prepared from the compound 3 wherein Ri is an aryl aldehyde by reductive amination under standard conditions.
Step 3
Thereafter the compound 3 is reacted with a reducing agent, such as lithium aluminum hydride or borane in an inert organic solvent, such as, tetrahydro-furan at from room temperature to reflux. If Ri or R2 contain functional groups, e.g., CO2R, which are reduced by, e.g. lithium aluminum hydride, to, e.g. CH2OH, these groups will also be reduced by step 3. The compound 4 or 6 wherein Ri is CN can be prepared from the compound 4 or 6 wherein R-j = halogen by displacement with CuCN in an inert solvent such as NMP at elevated temperature. The compound 4 wherein Ri is CO2H can be prepared from the compound 4 wherein Ri = CN by hydrolysis, e.g. by heating with aqueous sodium hydroxide in a suitable solvent such as ethanol at 100°C; thereafter the product wherein R1 = CONR5R6 may be prepared by standard amide bond coupling conditions.
Step 4
Thereafter the product is acylated or sulfonylated under standard conditions at from -78 C to room temperature (e.g., by reaction with an acid halide R3COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/dichloroethane; by reaction with an O-phenyl ester in an inert organic solvent, e.g. acetonitrile; by reaction with a carboxyiic acid in the presence of a coupling agent, e.g. DCC or EDC in an inert organic solvent, such as DMF; by reaction with a haloformate such as ethyl, isopropyl or 4- nitrophenylchloroformate in an inert solvent such as dichloromethane at from 0°C to room temperature in the presence of an optional base such as diisopropylethylamine to form carbamates, some of which, e.g. 4- nitrophenyl-carbamate, are reacted with an amine, e.g. N,N,N'- trimethylethylenediamine, at from room temperature to 110°C to form ureas; by reaction with a carboxyiic or sulfonyl anhydride such as succinic anhydride or trifluoromethanesulfonyl anhydride in an inert solvent such as ethyl acetate, dichloromethane or pyridine at from 0°C to room temperature in the presence of an optional base such as diisopropylethylamine; by reaction with an isocyanate in an inert solvent such as THF; by reaction with a carbamyl chloride R5R6NCOX wherein X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine/dimethyl-aminopyridine; by reaction with a sulfonyl halide R3SO2X wherein X is Cl or Br in a mixed aqueous/organic solvent e.g. NaOH/CH2Cl2; by reaction with a halosulfonate ROSO2X wherein X is Cl or Br in an inert solvent such as CH2CI2; by reaction with a sulfamoyl chloride R5R6NSO2X wherein X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine/dimethyl-aminopyridine; by reaction with an N-cyano- thiourea NH(CN)C(S)NRsR6 in the presence of a coupling reagent such as a carbodiimide in an inert solvent such as DMF at about room temperature; by reaction with a cyanocarbonimidate such as diphenylcyanocarbonimidate in a suitable solvent such as DMF in the presence of a base such as diisopropylethylamine at from room temperature to 80°C, followed by reaction with an amine such as methylamine at about room temperature). The compound 5 wherein Ri is halogen, e.g. bromine, may be prepared from the compound 5 wherein Ri = H by reaction with a halogenating agent, e.g. tetrabutylammonium perbromide, in an inert solvent such as chloroform at about room temperature. Where Ri or R2 contain CH2OH, the acylation may be performed in such a manner as to obtain the diamide ester; the ester may then be cleaved, e.g., by sodium methoxide in methanol and the resulting alcohol oxidized to an acid, e.g., by Jones reagent; the N1 amide may then be cleaved, e.g., by KOH in aqueous methanol at reflux, and the acid may be coupled with amines under standard peptide coupling conditions to form compounds 5 of Scheme 1 where R or R2 is a carboxamide. Where R or R2 contain CH2θ-Prot, the protecting group may be removed, e.g., Boc by treatment with an acid such as TFA in an inert solvent such as dichloromethane to form a compound 5 or 6 where Ri or R2 is CH2OH. The compound 5 where Ri or R2 is aryloxyalkyl is prepared from a compound 5 where Ri or R2 is CH2OH by transformation of the alcohol into a leaving group such as a trifiate. e.g., by treatment with triflic anhydride in dichloromethane at -40°C, and displacement with an aralkoxide salt, e.g., in dichloromethane at from -40°C to room temperature. The compound 5 where R or R2 is CH2NH2 is prepared from a compound 5 where R or R2 is CH2OH by transformation of the alcohol into a leaving group such as a trifiate. e.g., by treatment with triflic anhydride in dichloromethane at -40°C, and displacement with ammonia, e.g., in dichloromethane at from -40°C to room temperature. The amine may be subsequently coupled to carboxyiic acids by standard amide bond coupling conditions. Where the compound 5 is sulfonylated with a beta-haloalkylsulfonyl halide, the halide may then be eliminated by a base such as diisopropylethylamine and then nucleophiles such as dimethylamine or sodium imidazolate may be added to the resulting unsaturated sulfonamide by treatment in an organic solvent such as THF or dichloromethane at from room temperature to reflux. Where the compound 5 is acylated or sulfonylated with an acylating or sulfonylating agent which contains a leaving group, e.g. chloride or bromide, that leaving group may be displaced by nucleophiles, e.g., by amines such as dimethylamine or N- methylpiperazine in an inert solvent such as THF or DMF in the presence of an optional base such as diisopropylethylamine at from 0°C to 110°C. Thereafter the various products can undergo reductive alkylation in the presence of an acid e.g. acetic acid, a reducing agent e.g. NaBH(OAc)3 in an inert organic solvent e.g. dichloroethane at about room temperature. Reductive alkylation may also be performed using hydrogen and a catalyst such as Pd on carbon in a solvent such as ethanol in the presence of an acid such as acetic acid at about room temperature.
Thereafter, the compound of Scheme 1 where Ri = halogen can be metallated and quenched , e.g., with water to form the compound where Ri = H or with carbon dioxide to form the compound where Ri = CO2H; this acid may be coupled with amines under standard peptide coupling conditions to form compounds of Scheme 1 where Ri is a carboxamide. The compound of Scheme 1 wherein Ri = halogen can be metallated and quenched with a ketone such as cyclohexanone followed by reduction of the alcohol with for example trifluoroacetic acid/sodium borohydride to form the compound where R = e.g., cyclohexyl. The compound of Scheme 1 in which the imidazole contains a 2-dimethylaminomethyl group can be prepared by standard Mannich conditions. The compound of Scheme 1 in which Ri = OH can be prepared from the compound of Scheme 1 in which R = OMe by dealkylation, e.g., by treatment with BBr3. The compound of Scheme 1 in which R = arylOalkyl can be prepared from the compound of Scheme 1 in which R-| = HOalkyl by Mitsunobu reaction with the aryl alcohol. The compound of Scheme 1 in which R3 = aryl-NH2 or heteroaryl-NH2 can be prepared from the compound of Scheme 1 in which R3 = aryl-N02 or heteroaryl-Nθ2 by reduction (e.g., SnCl2) under standard conditions. The product can be further acylated, sulfonylated or reductively aminated under standard conditions.
Scheme 2
Figure imgf000019_0001
Zi = CO, SO2
Step 1
In Scheme 2 the starting material is reduced via hydrogenation in the presence of platinum oxide. The reaction is carried out in the presence of an alcohol e.g. ethanol at about room temperature.
Step 2 and 3
Thereafter the product is monoacylated or monosulfonylated under standard conditions at from -78 C to room temperature (e.g., by reaction with an acid halide R2COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/methylene chloride; or by reaction with a sulfonyl halide R3SO2X wherein X is Cl or Br in an organic solvent e.g. CH2CI2 in the presence of a base such as triethylamine). Thereafter the product undergoes a reductive alkylation as outlined in the last step of Scheme 1. Scheme 3
Figure imgf000020_0001
In Scheme 3, compound 1 is suitably protected by, for example, a tertbutoxycarbonyl group. The reaction is carried out in an inert organic solvent e.g. THF at about room temperature. The compound 2 where Ri is an amine may be selectively acylated, e.g., by reaction with isobutylchloroformate in an inert solvent such as methylene chloride in the presence of a base such as diisopropylethylamine at about room temperature. The compound 2 where an Ri is R5CONH and another Ri is Br is prepared from the compound where an R is R5CONH by bromination, e.g. with tetrabutylammonium tribromide in an inert solvent such as chloroform at about room temperature. Thereafter the compound 2 is reacted with a compound of the formula R3COCI in the presence of pyridine in an inert organic solvent, such as, dichloroethane at from about 0°C to room temperature. Thereafter the compound 3 is deprotected by reaction with, for example, trifluoroacetic acid in an inert organic solvent, such as, dichloroethane at about room temperature. Thereafter the compound 4 undergoes reductive alkylation following the steps outlined in Scheme 1.
Scheme 4
Figure imgf000021_0001
Figure imgf000021_0002
Zi = CO, so2
In Scheme 4 the compound 1 is reacted with a compound of the formula R2COCθ2Me in the presence of an organic acid e.g. acetic acid, a reducing agent, such as, NaCNBH3 or NaBH(OAc)3 in an inert organic solvent, such as, dichloroethane at about room temperature. The intermediate is thereafter deprotected by reaction with, for example, trifluoroacetic acid in an inert organic solvent, e.g. CH2CI2 at about room temperature, and cyclized by heating, e.g., at 60°C to form the compound 2. Thereafter the compound 2 undergoes reductive alkylation as outlined in Scheme 1 to form a compound 3. The compound 3 may be reduced, e.g. with lithium aluminum hydride, to a compound 4, which may be reacted to form a compound 6 as described in Scheme 12. Alternatively, the compound 2 is reduced to the compound 5, as outlined in Scheme 1 , and the compound 5 is reacted as outlined in Scheme 1.
Scheme 5
Figure imgf000022_0001
In Scheme 5 the compound 1 is protected by reaction with, for example, triphenylmethyl chloride or Boc anhydride in an inert organic solvent e.g. acetonitrile or tetrahydrofuran, from about room temperature to reflux. Thereafter the compound 2 is reacted with a compound of the formula R4-L wherein L is a leaving group such as trifiate, in the presence of a base such as diisopropylethylamine in an inert organic solvent such as tetrahydrofuran at from about -78 C to room temperature. R4 may contain a protecting group, e.g., phthalimide, removable by e.g. hydrazine. The reaction of Scheme 5 with R4-L may also be performed on a compound 1 to directly produce a compound 3 without protection/deprotection.
Scheme 6
Figure imgf000023_0001
Figure imgf000023_0002
In Scheme 6, a cyanoacetylamino acid is reacted with a dithianediol in a suitable solvent such as ethanol in the presence of bases such as piperidine and triethylamine at from room temperature to 80°C. The intermediate is then cyclized in a suitable solvent such as pyridine in the presence of a catalyst such as pyridinium hydrochloride at an elevated temperature such as 130°C. Thereafter the compound 2 is reacted as described in Scheme 1.
Scheme 7
Figure imgf000024_0001
Figure imgf000024_0002
Zi = CO, SO2, CO2, CONRg, SO2NR5
Ui = CO, SO2, CO2, CONR5, SO2NR5 or absent
The compound 1 of Scheme 7 undergoes reduction (e.g., Fe, SnCl2, or TiCl3) under standard conditions. The compound 2 is acylated or sulfonylated under standard conditions (e.g., by reaction with an anhydride and an acylation catalyst such as DMAP, by reaction with an acid halide, by reaction with a carboxyiic acid under standard peptide coupling conditions, by reaction with an alkoxycarbonylchloride, by reaction with an isocyanate, by reaction with a sulfonyl halide or by reaction with a sulfamyl chloride) or reductively alkylated under standard conditions (e.g., by reaction with an aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature). Scheme 8
Figure imgf000025_0001
Zi = CO, SO2, CONR5, SO2NR5
Figure imgf000025_0002
The compound 1 of Scheme 8 is reacted with an ethylenediamine and the product 2 undergoes reduction, selective acylation or sulfonylation and reductive alkylation to produce a compound 3 as outlined in Scheme 1. Alternatively, Step 1 of Scheme 8 may be performed in 2 steps, wherein the ethylenediamine is condensed with the halogenated heterocycle either neat or in an organic solvent at elevated temperature and the resulting amino acid is cyclized under standard amide bond forming conditions, e.g., using HOBt/carbodiimide in an organic solvent such as DMF or pyridine at from 0°C to room temperature. Some compounds 1 of Scheme 8 wherein Ri = halogen are not commercially available. Such compound 2 of Scheme 8 wherein Ri = halogen can be prepared from compound 2 of Scheme 8 wherein Ri = hydrogen by halogenation, for example by reaction with bromine in an organic solvent such as acetic acid at from 0°C to room temperature. The compound 2 wherein Ri = aryl or heteroaryl can be prepared from the compound 2 wherein Ri is halogen or trifluoromethanesulfonyloxy by standard Suzuki or Stille couplings as described for Step 2 of Scheme 1. Thereafter the product undergoes reduction, acylation or sulfonylation, and reductive alkylation as outlined in Scheme 1. Compound 2 of Scheme 8 may itself undergo reductive alkylation with an imidazole containing aldehyde as outlined in Scheme 1 to afford a target compound.
Scheme 9 (imidazole aldehydes)
Figure imgf000026_0001
Figure imgf000026_0002
Some imidazole aldehydes are prepared as follows. An imidazole containing aldehyde undergoes a Wittig reaction with a compound of the formula triethylphosphonoacetate in the presence of a base, such as, sodium hydride in an inert organic solvent, such as dimethoxyethane, at from about 0°C to room temperature. The product is hydrogenated in an alcohol e.g. ethanol at about room temperature and reduced by reaction with DIBAL in for example dichloroethane at about -78 C. Alternatively, some aminoalkyl containing imidazolylalkanols, prepared by known methods (e.g., Buschauer, et. al., Arch. Pharm., 315, 563, (1982)) are protected with a Boc group as in Scheme 3, step 1 , and undergo an oxidation, e.g. under Swern conditions.
Scheme 10
CH(NH2)CH2CHCH2
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
In Scheme 10 the starting material is reacted with allyl magnesium bromide in the presence of lithium hexamethyldisilazide in an inert solvent e.g. THF at from about -78 C to room temperature. The product is protected, e.g. with a Teoc group, in an aqueous/organic solvent e.g. aqueous dioxane at about room temperature. The product is oxidized by reaction with e.g. Osθ4/Nalθ4 in aqueous dioxane at about room temperature. Thereafter the product undergoes reductive alkylation as in Scheme 1 and thereafter the product is deprotected with tetrabutylammonium fluoride at from room temperture to 50 C in THF. Scheme 11
Figure imgf000028_0001
In Scheme 11 the starting material is reduced with e.g. lithium aluminum hydride in an inert organic solvent e.g. ethylene glycol dimethyl ether at from about 0°C to reflux. Scheme 12
Figure imgf000028_0002
O, S02l C02, CONR5,
Figure imgf000028_0003
In step 1 of Scheme 12, a monoprotected benzodiazepine such as that described in Scheme 3 is coupled with an optionally protected imidazole-containing carboxyiic acid using standard amide bond formation methods such as isobutylchloroformate in an organic solvent such as THF at from -30°C to room temperature. In step 2 of Scheme 12, the resulting amide is reduced with for example borane in an organic solvent such as THF at from room temperature to reflux. A compound 3 of Scheme 12 may contain a nitro group which may be reduced, e.g., by TiCl3, to an amine, which may then be acylated or sulfonylated as described in Scheme 7. In step 3 of Scheme 12, the amine protecting group is removed (e.g., Boc by an acid such as TFA in an organic solvent such as methylene chloride). In step 4 of Scheme 12, the resulting compound is reacted under standard conditions with a variety of active acylating or sulfonylating agents to form the claimed compound, such as acids under carbodiimide conditions or acid chlorides to form amides; carbonates or chloroformates to form carbamates; carbamyl chlorides or isocyanates to form ureas; sulfonyl chlorides to form sulfonamides; halosulfonates to form sulfamates; sulfamoyl chlorides to form sulfonylureas. In step 4 of Scheme 12, the resulting compound is alternatively reacted under standard reductive amination conditions with aldehydes as described in Step 5 of Scheme 1 to form the claimed compounds. If the imidazole is optionally protected, it is then deprotected.
Scheme 13
2
Figure imgf000029_0001
In step 1 of Scheme 13, a monoprotected benzodiazepine such as that described in Scheme 3 is reductively alkylated with an imidazole- containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature.
Thereafter, the product is reacted as described in Scheme 12. The product 2 may be attached to a solid support, e.g. polystyrene resin, and the reactions of Scheme 1 may be performed on resin-bound material. Removal from the support, e.g. by treatment with an acid such as trifluoroacetic acid in the presence of a scavenger such as triethylsilane at about room temperature, then provides the compound 6 of Scheme 1. Scheme 14
Figure imgf000030_0001
e.g., Scheme 1 or 3
Figure imgf000030_0002
In step 1 of Scheme 14, an aminobenzoic acid is reductively aminated with an N-protected aminoaldehyde under standard conditions, e.g. by reaction with a hydride reagent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride or methanol in the presence of an acid such as acetic acid at from 0°C to about room temperature. The product is deprotected by, e.g., removal of Boc by treatment with an acid such as TFA or HCl in the presence of an optional scavenger such as dimethylsulfide in a suitable solvent such as methylene chloride or dioxane at about room temperature or removal of Fmoc by treatment with a secondary amine in tetrahydrofuran at about room temperature. Thereafter, the product is cyclized under standard amide bond forming conditions, such as by treatment with diphenylphosphoryl azide in an organic solvent such as DMF. Thereafter, the product is reacted as described in Scheme 1. Scheme 15
Scheme 1
Figure imgf000031_0001
1 2
In step 1 of Scheme 15, a benzodiazepinedione is sulfonylated with chlorosulfonic acid and the resulting sulfonyl chloride is condensed with an amine. Thereafter, the product is reacted as described in Scheme 1.
Scheme 16
Figure imgf000031_0002
In step 1 of Scheme 16, a benzodiazepine of Scheme 1 can be doubly reductively alkylated with an imidazole containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0°C to room temperature.
Scheme 17
Figure imgf000032_0001
In step 1 of Scheme 17, a benzodiazepine of Scheme 1 can be reacted with R3-L in an inert solvent such as DMF, THF or methylene chloride in the presence of a base such as diisopropylethylamine or potassium carbonate at from 0°C to 100°C, where L is a leaving group such as chloride, bromide, mesylate, tosylate or trifiate and R3 is a substituted alkyl group, a substituted aryl group or a substituted heterocylic group. Thereafter, the product is reacted as described in Scheme 1.
Scheme 18
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
e.g., Scheme 1 or 3
Figure imgf000033_0004
8
Step 1
The first step is accomplished by the reaction of a pyridine containing a protected amino group and a methyl group with an oxidizing agent, such as hydrogen peroxide in a suitable solvent such as aqueous acetic acid or trifluoroacetic acid at from room temperature to 75°C.
Step 2
The product is acylated with an acylating agent such as acetic anhydride and rearranged by heating from room temperature to 90°C in a suitable solvent such as acetic acid. Step 3
The product is deacylated, e.g., with aqueous NaOH at from room temperature to 50°C and oxidized to the aldehyde with e.g. Mnθ2 in a suitable solvent such as tetrahydrofuran at about room temperature.
Step 4
The product is reductively aminated with an aminoacid ester under standard conditions, e.g., by hydrogenation in an inert solvent such as methanol or by reaction with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
Step 5 The product is deprotected and cyclized with, e.g. treatment with polyphosphoric acid at from room temperature to 100°C.
Step 6
The product is sulfonylated as described for Step 4 of Scheme 1.
Step 7
The product is reduced as described for Step 3 of Scheme 1. Thereafter, the product is reacted as described in Step 5 of Scheme 1
Scheme 19
e.g., Scheme 14,
Figure imgf000034_0001
The first step is accomplished by the reaction of a pyrimidine containing a halide and a carboxyiic acid group with an optionally monoprotected diamine in a suitable solvent such as water in the presence of a catalyst such as CuSθ4 at from room temperature to 100°C. Thereafter, the product is reacted as described in Scheme 14. Scheme 20
Figure imgf000035_0001
Figure imgf000035_0002
Step 1
The first step is accomplished by reductive amination of a nitrobenzaldehyde with an amino acid ester under standard conditions, e.g., by reaction with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
Step 2
The product is sulfonylated as described for Step 4 of Scheme 1. Step 3
The nitro group of the product is reduced to an amine under standard conditions, such as reaction with SnCl2 or TiCl3. The compound where Ri = Br may be prepared from the compound where Ri = H by bromination, such as reaction with tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. Step 4
The product is cyclized by heating with CuCN in an inert solvent such as N-methylpyrrolidinone at from room temperature to 195°C. The compound where Ri = CN is prepared from the compound where Ri = halogen under the same conditions.
Step 5
The product is alkylated with an optionally protected imidazolylalkanol under Mitsunobu conditions. Thereafter, the product is optionally reacted as described in Scheme 5.
Scheme 21
Figure imgf000036_0001
Figure imgf000036_0002
A compound 3 of Scheme 1 may be selectively reduced, e.g. by reaction with a reducing agent, such as borane in an inert organic solvent, such as, tetrahydrofuran at about room temperature. Thereafter, the product (2) is reductively aminated as described in Scheme 1. Scheme 22
Figure imgf000037_0001
Figure imgf000037_0002
3
Step 1
A compound 4 of Scheme 20 may be first reductively aminated as described in Step 5 of Scheme 1.
Step 2
The optionally esterified ester of the product is hydrolyzed, e.g. by reaction with an alkali hydroxide in a suitable solvent such as aqueous alcohol at from room temperature to reflux.
Step 3
The product is cyclized by standard amide bond forming conditions, e.g. by reaction with BOP in an inert solvent such as DMF in the presence of an optional base such as diisopropylethylamine at about room temperature.
Scheme 23
Figure imgf000038_0001
Figure imgf000038_0002
A compound 2 of Scheme 12 may be directly deprotected as described in Step 3 of Scheme 12 and reacted as described in Step 4 of Scheme 12. Alternatively, a compound 5 of Scheme 12 may be prepared by reduction, e.g. with lithium aluminum hydride or borane, of a compound 3 of Scheme 23, where Zi does not equal CO.
Scheme 24
Figure imgf000039_0001
Z! = S02, SO2NR5
A compound 5 of Scheme 1 may be reacted with an imidazole containing aldehyde and an alkali cyanide such as NaCN in the presence of an acid such as acetic acid in a suitable solvent such as methanol/acetonitrile at about room temperature to form a compound 2. The compound 2 may be reduced, e.g. with lithium aluminum hydride, in a suitable solvent such as ether at about room temperature to form a compound 3. The compound 3 wherein Ri is halogen, e.g. bromine, may be prepared from the compound 3 wherein R = H by reaction with a halogenating agent, e.g. tetrabutylammonium perbromide, in an inert solvent such as chloroform at about room temperature. The compound 3 may be reductively aminated under standard conditions to form the compound 4.
Figure imgf000040_0001
Figure imgf000040_0002
ZΛ = S02, C02
In step 1 of Scheme 25, an N-(2-nitroaryl)-amino acid ester, available by reaction of an amino acid with a 1 -fluoro-2-nitrobenzene followed by esterification, is reduced, e.g. with hydrogen and a palladium catalyst in a suitable solvent such as ethyl acetate at about room temperature. The resulting amine is cyclized to a compound 2 under the reduction conditions. The compound 2 is acylated or sulfonylated as described in Step 4 of Scheme 1. The compound 3 is reduced, e.g. with borane in a suitable solvent such as methanol at about room temperature. The compound 3 wherein Ri is halogen, e.g. bromine, may be prepared from the compound 3 wherein R = H by reaction with a halogenating agent, e.g. tetrabutylammonium perbromide, in an inert solvent such as chloroform at about room temperature. The compound 4 undergoes reductive amination with an imidazole containing aldehyde as described in Step 5 of Scheme 1. Scheme 26
Figure imgf000041_0001
In step 1 of Scheme 26, the compound 1 is reacted with a methylenating agent such as N,N,N'N'-tetramethyl-diaminomethane in a suitable solvent such as acetic anhydride and DMF at about room temperature. Thereafter, the compound 2 is reacted with a 1 ,2- phenylenediamine in a suitable solvent such as toluene at about 115°C under dehydrating conditions, e.g. with a Dean-Stark trap, in the presence of a hydroquinone. Thereafter, the compound 3 is both reduced and reductively aminated as described in Step 5 of Scheme 1.
The invention will now be further described by the following working examples(s), which are preferred embodiments of the invention. All temperatures are in degrees Celsius (°C) unless otherwise indicated. These examples are illustrative rather than limiting. Example 1
Figure imgf000042_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenyicarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
A. 1 ,4-Benzodiazepine-2,5-dione. A stirred solution of isatoic anhydride (16.4 g, 0.1 mol) and glycine ethyl ester hydrochloride in 40 mL of pyridine was heated under reflux for 7 h. The resulting suspension was cooled to 0°C for 18 h. The precipitate was collected and washed with ethanol and ether to give Compound A as a light yellow solid.
B. 2,3,4,5-Tetrahydro-1 H-1 ,4-benzodiazepine
To a stirred suspension of lithium aluminum hydride (LAH, 3.5 g, 90 mmol) in THF (100 mL) at room temperature under argon was slowly added Compound A (3.5 g, 20 mmol) portionwise as a solid. After the addition, the resultant suspension was heated at reflux under argon for 18 h, cooled to 0°C, and a mixture of NH4OH (5 mL, cone.) in 30 mL of THF was added via an additional funnel. The resultant suspension was stirred for 1 h and filtered. The filtrate was concentrated in vacuo to give Compound B as an oil.
C . 2,3,4,5-Tetrahydro-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine A mixture of Compound B (500 mg, 3.37 mmol) and 1-naphthoic acid, phenyl ester (750 mg, 3.02 mmol) in a small amount of acetonitrile in the presence of a catalytic amount of dimethylaminopyridine (DMAP) was heated at 110°C for 18 h under argon. The mixture was cooled to room temperature. The product was isolated by flash column chromatography (1 :1 ethyl acetate:hexanes) to give Compound C as a white solid (520 mg).
D . 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride To a stirred solution of Compound C (200 mg, 0.66 mmol) and 4- formylimidazole (110 mg, 1.15 mmol) in a mixture of dichloroethane (2 mL) and acetic acid (1.0 mL), NaBH(OAc)3 (190 mg) was added in one portion.
The mixture was stirred for 30 min and diluted with ethyl acetate (25 mL) followed by NH4OH (3 mL, cone). The mixture was stirred at room temperature for 18 h and poured into a mixture of ethyl acetate (50 mL) and sat. NaHCθ3 (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with sat. NH4CI solution (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in methanol (2 mL), and 1 N HCl solution in ether (2 mL) was added. The solvent was removed in vacuo and the residue was dried under vacuum to give Example 1 as a light yellow solid (240 mg). MS: (M+H)+ 383+ Analysis calculated for C24H22N4O »1.75 HCl «2.5 H2O.
Calc'd: C, 58.67; H, 5.90; N, 11.41 ; Cl, 12.63. Found: C, 58.48; H, 6.10; N, 11.32; Cl, 12.46.
Example 2
Figure imgf000044_0001
8-Chloro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride
A. 8-Chloro-1 ,4-benzodiazepin-2,5-dione
A solution of 7-chloro-isatoic anhydride (34 g, 0.17 mol) and glycine ethyl ester hydrochloride (24 g, 0.17 mol) in anhydrous pyridine (120 ml) was warmed at 80°C for 1 hour and refluxed overnight. The resulting suspension was stirred at room temperature for 3 hrs. The precipitate was filtered, washed with water and dried to give 4.4 g of Compound A as a white solid. The filtrate was evaporated and the resulting solid was washed with water and dried to provide an additional 27.2 g of Compound A as a white solid (85% total yield). MS (M+H) 211.
B. 8-Chloro-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine
To Compound A (1.4 g, 6.6 mmol) in ethylene glycol dimethyl ether (20 ml) was added borane-THF (1.0 M in THF, 20 ml). The clear solution was refluxed for 6 hrs. The solvent was evaporated and the residue was treated with sat. sodium bicarbonate. The aqueous solution was extracted with methylene chloride. The organic solution was washed with sat. sodium bicarbonate and brine, dried (sodium sulfate) and evaporated to afford an oil (1.0 g). The crude product was purified by chromatography (10% methanol in methylene chloride) to provide Compound B as a slightly yellow solid (0.56 g, 46%). MS (M+H) 183.
C . 8-Chloro-2,3,4,5-tetrahydro-4-(1 -naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepine
To a solution of Compound B (0.154 g, 0.84 mmol) in methylene chloride (4 ml) and sodium hydroxide (1 N, 4 ml) at 0°C was added 1 -naphthoyl chloride (0.12 ml, 0.84 mmol) in methylene chloride (1 ml) dropwise. The solution was stirred for 1 hour, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried (sodium sulfate) and evaporated. The resulting oil was chromatographed (silica, 5% methanol, 0.5% ammonium hydroxide, 94.5%methylene chloride) to provide Compound C as a yellow solid (0.26 g, 90%). MS (M-H) 335.
D . 8-Chloro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride
Compound D was prepared from Compound C as described for Compound D of Example 1. Chromatography (silica, 5% methanol, 0.5%ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt provided Example 2 as an off white solid, m.p. 160-162°C. MS: (M+H)+ 383+ Analysis calculated for C24H21N4OCI «1.85 HCl »2.5 H2O.
Calc'd: C, 59.51 ; H, 4.76; N, 11.57. Found: C, 59.42; H, 4.84; N, 11.48.
Example 3
Figure imgf000045_0001
1 ,2,3,4-Tetrahydro-4-[(3H-imidazol-4-yl)methyl]-1 -(naphthalen-1 ylcarbonyl)quinoxaline, dihydrochloride.
A. 1 ,2,3,4-Tetrahydro-quinoxaline
Pt(IV)O2 (Adams' catalyst, 200 mg) was added to a solution of quinoxaline (2.75 mg, 21 mmol) in absolute EtOH (100 mL) and the mixture was hydrogenated (1 atm) at rt for 6 hrs. The mixture was fitered through Celite and the filtrate was concentrated to give 2.74 g of Compound A as an off- white solid (97%). MS (M+H) 135. B. 1 ,2,3,4-Tetrahydro-1 -(naphthalen-1 - ylcarbonyl)quinoxaline
Naphthoyl chloride (1.12 mL, 7.45 mmol) was added to a solution of Compound A (1.0g, 7.45 mmol) and triethylamine (TEA, 2.1 mL, 14.9 mmol) in CH2CI2 (100 mL) at -78 °C. After 2 hrs, the cooling bath was removed the mixture was stirred at rt for 1 hr and concentrated. The residue was purified by flash chromatography (silica, 95:5:0.1 , CHCl3:MeOH:NH4θH) to afford
Compound B as an off-white solid (2.04 g, 95%). MS (M+H) 289.
C . 1 ,2,3,4-Tetrahydro-4-[(3H-imidazol-4-yl)methyl]-1 -
(naphthalen-1 -ylcarbonyl)quinoxaline, dihydrochloride
Compound C was prepared from Compound B as described for Compound D of Example 1. Chromatography (silica, 10% ethanol/ethyl acetate) provided a clear yellow oil which was converted to the hydrochloride with 4N HCl in dioxane (4mL, rt for 2 hrs) to give Example 3 as an off-white solid. MS: (M+H)+ 289+ Analysis calculated for C23H20N4O #1.9 HCl.
Calc'd: C, 63.10; H, 5.04; N, 12.47. Found: C, 63.10; H, 5.39; N, 12.47.
Example 4
Figure imgf000046_0001
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-yl-methyl)-1 -(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride,
A. 2,3,4,5-Tetrahydro-4-[(1 ,1 -dimethylethoxy)-carbonyl]-1 H-
1 ,4-benzodiazepine
To a stirred solution of Compound B of Example 1 (300 mg) was added di-t- butyldicarbonate (400 mg). The mixture was stirred at room temperature for 18 h and quenched by the addition of sat. NaHCO3 solution. The solvent was removed and the residue was chromatographed (flash, silica, 1 :2 ethyl acetate :hexanes] to give Compound A as an oil (350 mg).
B. 2,3,4,5-Tetrahydro-1 -(1 -naphthalenylcarbonyl)-4-[(1 ,1 - dimethylethoxy)-carbonyl]-1 H-1 ,4-benzodiazepine
To a stirred solution of Compound A (350 mg, 1.4 mmol) in methylene chloride at 0°C under argon, was added 1 -naphthoyl chloride (0.22 mL, 1.4 mmol), followed by pyridine (0.25 ml). The mixture was stirred for 2 h. Sat. NaHCO3 was added and the mixture was stirred for 18 h at room temperature. The resultant solution was poured into a mixture of methylene chloride and sat. NaHC03. The organic layer was separated, washed with 10% HCl (2 x 25 mL), dried (MgS04) and concentrated in vacuo to give to give Compound B as an oil (450 mg, 80%).
C . 2,3,4,5-Tetrahydro-1 -(1 -naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine
Compound B was dissolved in a mixture of methylene chloride and TFA (10 mL, 1 :1). The solution was stirred at room temperature for 2 h. The solvent was removed in vauo, the residue was diluted in CHCI3 and made basic with 10 N NaOH solution. The organic layer was separated, dried (MgSO4) and concentrated to give Compound C as an oil (310 mg, 92%).
D 2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-yl-methyl)-1-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride Example 4 was prepared as a light yellow solid from Compound C as described for Compound D of Example 1. Analysis calculated for C24H22N4O -2.0 HCl »1.3 H2O.
Calc'd: C, 60.20; H, 5.60; N, 11.70; Cl, 14.82. Found: C, 60.21 ; H, 5.60; N, 11.48; Cl, 14.68.
Example 5
Figure imgf000048_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-2-methyl-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
A. 2-Methyl-1 ,4-benzodiazepin-3-one
The Boc derivative of Compound A was prepared from 2-amino-N-[(1 ,1- dimethylethoxy)-carbonyl]-phenylmethylamine and methyl pyruvate as described for Compound D of Example 1. The resulting oil was dissolved in a mixture of methylene chloride and TFA (8 mL, 1 :1), the solution was stirred at room temperature for 1 h and concentrated in vacuo. The residue was partitioned between ether and 10% HCl solution and the aqueous solution was made basic with 10N NaOH solution to pH 11 and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over MgSθ4 and concentrated to give Compound A as a solid (250 mg, 28%), mp: 149- 151 °C. MS (M+H) 177.
B. 2-Methyl-1 ,4-benzodiazepine
A solution of Compound A (181 mg, 1.03 mmol) was added to a suspension of LAH (160 mg, 4.21 mmol) in anhydrous THF(5 mL) at room temperature dropwise. The solution was heated at reflux for 5 h, cooled to 0°C and diluted with THF (20 mL). Brine (0.5 mL) was added dropwise and the mixture was stirred at room temperature for 18h and filtered through a pad of MgSθ4. The pad was washed with ethyl acetate and the combined filtrates were concentrated in vacuo to give Compound B as a semisolid (160 mg, 96%). MS (M+H) 163. C . 2-Methyl-4-(1-Naphthalenylcarbonyl)-1 ,4- benzodiazepine
Compound C was prepared from Compound B as described for Compound C of Example 2. Chromatograpy (flash, silica, 1 ;1 ethyl acetate: hexanes) gave Compound C a solid, mp: 75°C. MS (M+H) 317.
D . 2,3,4,5-Tetrahydro-1-(1H-imidazol-4-yl-methyl)-2-methyl- 4-(1-naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride Example 5 was prepared as a light yellow solid from Compound C as described for Compound D of Example 1 , mp: 165°C (foams). MS (M+H) 397. Analysis calculated for C25H24N4O «2.4 HCl »1.0 H2O -0.5 CH3OH.
Calc'd: C, 59.12; H, 5.92; N, 10.84; Cl, 16.42. Found: C, 59.09; H, 5.58; N, 10.48; Cl, 16.28.
Example 6
Figure imgf000049_0001
2,3,4,5-Tetrahydro-4-(1 -naphthalenylcarbonyl)-1 -[[1 - (phenylmethyl)-l H-imidazol-5-yl]methyl]-1 H-1 ,4-benzodiazepine, hydrochloride.
A. 2,3,4,5-Tetrahydro-4-(1-naphthalenylcarbonyl)-1 -[[1 -
(triphenylmethyl)-l H-imidazol-4-yl]methyl]-1 H-1 ,4- benzodiazepine
To a solution of Example 1 (90 mg, 0.21 mmol) in acetonitrile (1 ml) at rt under argon was added TEA (0.14 μL, 1 mmol) followed by triphenylmethylchloride ( 56 mg, 0.2 mmol). The mixture was refluxed for 2 hr, cooled to rt and stirred for 14 hr. The precipitate was filtered and the filtrate was concentrated to afford Compound A (110 mg, 92 %). MS (M+H)+ = 625.
B. 2,3,4,5-Tetrahydro-4-(1 -naphthalenylcarbonyl)-1 -[[1 - (phenylmethyl)-l H-imidazol-5-yl]methyl]-1 H-1 ,4-benzodiazepine, hydrochloride
To a solution of benzyl alcohol (18 μL, 0.18 mmol) in THF (1 ml) at -78°C under argon was added triflic anhydride (30 μL, 0.18 mmol) and DIPEA (35 μL, 2 mmol). After 20 min, a THF (1 ml) solution of Compound A (100 mg, 0.15 mmol) was added dropwise. The mixture was allowed to warm to rt over 3 hr and was stirred for 14 hr. Acetic acid (1.5 ml) and water (1 ml) were added and the mixture was refluxed for 30 min, cooled to rt and evaporated. The residue was dissolved in chloroform and the solution was washed with saturated NaHCθ3 solution, dried (MgSO4) and concentrated. The residue was chromatographed (flash, silica, 9:1 CHCl3:MeOH). Clean product was dissolved in ethyl acetate and the solution was bubbled with HCl gas for 30 seconds. Evaporation afforded Example 6 (33 mg. 33% overall). MS (M+H)+ = 473- IR (KBr) 2853, 1630, 1508 cm-1
Example 7
Figure imgf000050_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-4-(1 - naphthalenylsulfonyl)-1 H-1 ,4-benzodiazepine, hydrochloride,
A. 2,3,4,5-Tetrahydro-4-(1 -naphthalenylsulfonyl)-1 H-1 ,4- benzodiazepine
Compound A was prepared from Compound B of Example 1 and 1 - naphthalenesulfonyl chloride as described for Compound C of Example 2. Crystallization from methanol gave Compound A as a solid, mp 165-166 °C. MS (M+H) 339. B. 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-yl-methyl)-4-(1 - naphthalenylsulfonyl)-1 H-1 ,4-benzodiazepine, hydrochloride
Example 7 was prepared as a white solid from Compound A as described for Compound D of Example 1 , mp 140 °C (foams). MS (M+H) 419.
Analysis calculated for C23H22N4O2S »1.5 HCl «1.0 H2O.
Calc'd: C, 56.34; H, 5.22; N, 11.43; Cl, 10.85; S, 6.54. Found: C, 56.70; H, 5.16; N, 11.04; Cl, 10.72; S, 6.54.
Example 8
Figure imgf000051_0001
(S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[2- (methylthio)ethyl]-4-(1-naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Example 8 was prepared as a yellow solid from isatoic anhydride and L- methionine methyl ester hydrochloride as described in the following multistep sequence: Compound A of Example 1 ; Compound B of Example 1 , except that ethylene glycol dimethyl ether was used as solvent; Compound C of Example 2; Compound D of Example 1. mp 78-80°C. MS (M+H) 457 Analysis calculated for C27H28N4OS »1.6 HCl «2.3 H2O.
Calc'd: C, 58.28; H, 6.20; N, 10.07; S, 5.76; Cl, 10.19. Found: C, 58.02; H, 5.87; N, 12.23; S, 4.95; Cl, 10.27. Example 9
Figure imgf000052_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-N-methyl-N- phenyl-4H-1 ,4-benzodiazepine-4-carboxamide, hydrochloride,
A. 2,3,4,5-Tetrahydro-N-methyl-N-phenyl-4H-1 ,4- benzodiazepine-4-carboxamide To a stirred solution of the Compound B of Example 1 (0.5 g, 3.35 mmol) in THF in the presence of NaHC03 (1.68, 20 mmol) was added N-methyl-N- phenyl carbamoyi chloride (480 mg, 2.83 mmol). The mixture was stirred at room temperature for 18 h and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from methanol to give Compound A as a white solid (720 mg, 76%), mp: 159-160 °C.
B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-N- methyl-N-phenyl-4H-1 ,4-benzodiazepine-4-carboxamide, hydrochloride Example 9 was prepared as a white solid from Compound A as described for Compound D of Example 1 , mp: 145°C (shrinks). MS (M+H) 362 Analysis calculated for C21H23N5O «1.8 HCl »1.0 H2O.
Calc'd: C, 56.67; H, 6.07; N, 15.74; Cl, 14.34. Found: C, 57.08; H, 6.03; N, 15.40; Cl, 14.53.
Example 10
Figure imgf000053_0001
2-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-yl-methyl)-1 H-1 ,4- benzodiazepin-4-yl]sulfonyl]benzoic acid, methyl ester, hydrochloride,
Example 10 was prepared as a white solid from 2- methoxycarbonylbenzenesulfonyl chloride and Compound B of Example 2 as described in the following multistep sequence: Compound C of Example 2; Compound D of Example 1. MS (M+H) 427 Analysis calculated for C21 H22N4O4S »1.1 HCl •1.0 H2O. Calc'd: C, 52.04; H, 5.22; N, 11.56; S, 6.62; Cl, 8.05. Found: C, 52.20; H, 5.11 ; N, 10.40; S, 7.20; Cl, 8.09.
Example 11
Figure imgf000053_0002
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride. A. 7-Bromo-1 ,4-benzodiazepin-2,5-dione
Compound A was prepared from 6-bromoisatoic anhydride as described for Compound A of Example 1.
B. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 8 was prepared as a solid from Compound A as described in the following multistep sequence: Compound B of Example 2; Compound C of Example 2; Compound D of Example 1. Chromatography (5% methanol, 0.5%ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion into the hydrochloride salt provided Example 11 , mp 160-162°C. MS (M+H) 461 Analysis calculated for C24H21 BrN4θ »1.5 HCl.
Calc'd: C, 55.86; H, 4.39; N, 10.86. Found: C, 55.84; H, 4.49; N, 10.71.
Example 12
Figure imgf000054_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride. A. 7-Phenyl-1 ,4-benzodiazepin-2,5-dione
A solution of Compound A of Example 11 (0.834 g, 3.1 mmol) in 20 mL of 1 :1 DMF:THF was degassed with nitrogen. Tetrakistriphenylphosphine palladium was added. After half an hour, anhydrous sodium carbonate (0.37 g, 3.5 mmol) in water (6 ml) and phenylboronic acid (1.00 g, 8.3 mmol) were added. The suspension was stirred at room temperature overnight, then at 80-90°C for 2 days. The suspension was filtered. The precipitate was washed with water and ethyl acetate to give a Compound A as slightly grey solid (0.65 g, 84%). LC-MS (M+H)+ 253.
B. 7-Phenyl-1 ,4-benzodiazepine
To a suspension of Compound A (0.62 g, 2.5 mmol) in THF was added LAH in THF (1.0 M in THF, 7 ml). The suspension was stirred for 3 hrs and refluxed for 2 hrs. After cooling to rt, sodium hydroxide (1 N, 5 ml) was added followed by 10 mL of saturated sodium potassium tartrate. The aqueous solution was extracted with methylene chloride. The organic phase was dried (sodium sulfate) and evaporated. The resulting oil was purified by chromatography (10% methanol in methylene chloride) to provide Compound B as a slightly yellow solid (0.46 g, 58%). LC-MS (M+H)+ 225.
C . 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 12 was prepared as a solid from Compound B as described in the following multistep sequence: Compound C of Example 2; Compound D of Example 1. Chromatography (5% methanol, 0.5%ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion into the hydrochloride salt provided Example 12, mp 158-160°C. MS (M+H) 459 Analysis calculated for C30H26N4O »2.0 HCl -0.58 H2O.
Calc'd: C, 66.50; H, 5.42; N, 10.34. Found: C, 66.56; H, 5.64; N, 10.00. Example 13
Figure imgf000056_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-2-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
To a solution of Compound C of Example 1 (50 mg, 0.085 mmol) in dichloroethane (5 mL) was added 2-imidazole carboxaldehyde (33 mg, 0.34 mmol), NaBH(OAc)3 (72 mg, 0.34 mmol) and glacial acetic acid (0.2 mL).
The mixture was stirred for 16 hr. Saturated aqueous sodium bicarbonate solution was added (0.5 mL) and the solution was concentrated to dryness. The residue was dissolved in a 50/50 mixture of 0.1%TFA in methanol and 0.1%TFA in water and applied to a YMC C18 column (S-5, ODS 30x250 mm). HPLC purification was performed under the following conditions; Solvent A; 0.1%TFA in 90% water, 10% methanol, Solvent B; 0.1%TFA in 90% methanol, 10% water; 10-90%B in A over 30 minutes. Fractions containing the major peak were pooled and lyophilized to afford a white solid. 1 M HCl (6 mL) was added and the solution was concentrated to a glass. This step was repeated to give 25 mg (66%) of Example 13 as a glassy white solid.
MS (M+H)+ 383
1 H-NMR (CD3OD, 270 MHz) d 8.11 (2H, m), 7.7-7.1 (10H, m), 6.71 (0.5H, t,
J=7.05 Hz), 6.07 (0.5H, d, J=7.05 Hz), 5.01 (1 H, m), 4.7-4.0 (2H, m), 3.6- 3.4(4H, m), 3.1(1 H, m).
Example 14
Figure imgf000057_0001
2,3,4,5-Tetrahydro-1 -[3-(1 H-imidazol-2-yl)propyl]-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 3-[lmidazol-2-yl]-propenoic acid, ethyl ester
To a cooled (0°C) solution of sodium hydride (1.86g, 45.8 mmol, 60% dispersion in mineral oil, prewashed with THF and dried over N2) in 1 ,2- dimethoxyethane (DME, 20 mL) was added triethylphosphonoacetate (12g, 54.1 mmol) dissolved in DME (10 mL) dropwise over 15 minutes. The solution was stirred for 1 hr at ambient temperature followed by the addition of 2-imidazole acetaldehyde (4 g, 41.6 mmol) in 20 mL of DME. The solution was stirred and heated to reflux (85°C) for 15 minutes followed by cooling to 60°C for 1 hr. On cooling, the solution was concentrated to 1/2 volume and filtered. The solid was recrystallized from methanol/ethyl acetate/hexanes to give 5.1g (74%) of Compound A as a white crystalline solid. MS (M+H)+ 167+.
B. 3-[lmidazol-2-yl]-propanoic acid, ethyl ester
A solution of Compound A (4.01 g, 24.2 mmol) in absolute ethanol (100 mL, heated to dissolve) was hydrogenated using Pd/C (0.5g) at ambient temperature for 16 hr. Following removal of H2 under vacuum, the catalyst was removed by filtration through a bed of celite. The filtrate was concentrated under vacuum to give 4.0 g (100%) of Compound B as a white crystalline solid. MS (M+H)+ 169+.
C . 3-[N-Triphenylmethyl-imidazol-2-yl]-propanoic acid, ethyl ester
Compound C was prepared from Compound B as described for Compound A of Example 6, using methylene chloride as solvent. After aqueous workup, recrystallization from ethyl acetate/hexanes afforded Compound C as a white crystalline solid. MS (M+H)+ 411+.
D . 3-[N-Triphenylmethyl-imidazol-2-yl]-propanal A stirred solution of Compound C (300 mg, 0.73 mmol) in dichloromethane (3 mL) was cooled to -78°C and a precooled (-70°C) solution of 1M DIBAL in dichloromethane (0.73 mmol, 0.73 mL) was introduced via syringe. After stirring for 1 h, an additional aliquot of precooled (-70°C) DIBAL solution (0.3 mL , 0.3 mmol) was added. After stirring for an additional 2 h, saturated aqueous NH4CI was added (10 mL) followed by 0.1 N HCl (20 mL). After stirring for 5 min, methylene chloride was added (30 mL). The layers were separated and the aqueous layer was washed with methylene chloride. The pooled organic layers were dried over MgS04, filtered and concentrated to yield 266 mg (99%) of Compound D as a white solid. 1H-NMR(CD3OD, 270 MHz) d 9.4(1 H, s), 7.38 (10H, m), 7.05 (7H, m), 2.7-2.2(4H, m).
E . 2,3,4,5-Tetrahydro-1 -[3-(1 -triphenylmethyl-imidazol-2- yl)propyl]-4-(1 -naphthaienylcarbonyl)-1 H-1 ,4-benzodiazepine
Compound E was prepared from Compound D and Compound C of Example 1 as described for Compound D of Example 1 , with stirring for 16 hours. Chromatography (flash, silica, 9:1 methylene chloride:methanol) afforded (74%) of Compound E as a glass. MS (M+H)+ 653.3.
F. 2,3,4,5-Tetrahydro-1 -[3-(1 H-imidazol-2-yl)propyl]-4-(1 - naphthalenylcarbonyl)-1H-1 ,4-benzodiazepine, dihydrochloride
A mixture of Compound E (110 mg, 0.18 mmol) in TFA (5 mL), methylene chloride (5 mL) and triethylsilane (0.1 mL) was stirred for 2 h at room temperature and concentrated. Hexanes was added with stirring to the residue and the mixture was decanted. The residue was dissolved in a 50/50 mixture of 0.1%TFA in methanol and 0.1%TFA in water and was applied to a YMC C18 column (S-5, ODS 30x250 mm) and HPLC purification was performed under the following conditions; Solvent A; 0.1%TFA in 90% water, 10% methanol, Solvent B; 0.1%TFA in 90% methanol, 10% water; 0-100%B in A over 30 minutes. Fractions containing the major peak were pooled and lyophilized to an oily residue. 1 M aqueous HCl (6 mL) was added and the solution was concentrated to a glass. This step was repeated to give 50 mg (84%) of Example 14 as a white solid. MS (M+H)+ 411.
1 H-NMR (CD3OD, 300 MHz) d 8.05-7.95 (2H, m), 7.6-7.05 (12H, m), 6.71
(0.5H, m), 6.02(0.5H, m), 4.4 (2H, m), 3.6-3.0 (8H, m), 2.2-2.0(2H, m).
Example 15
Figure imgf000059_0001
1 -[3-Amino-3-(1 H-imidazol-2-yl)propyl]-2,3,4,5-tetrahydro-4-(1 - naphthalenyicarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
A. N-[2-(trimethylsilyl)ethoxymethyl]imidazole
To a mixture of NaH (2.1g, 51 mmol, 60% dispersion in mineral oil, prewashed with hexanes) and DMF (60 mL) was added imidazole (3.0g, 44 mmol) in small portions. The mixture was stirred under N2 for 1 h followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (SEM-CI) dropwise. The mixture was stirred for 1 h and quenched with water (5 mL). The mixture was poured into water (80 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NH4CI, brine, dried (MgS04), filtered and concentrated to yield 6.3g (72%) of Compound A as a clear liquid. MS (M+H)+ 199.
B. N-[2-(trimethylsilyl)ethoxymethyl]imidazole-2- carboxaldehyde To a cooled (-40°C) mixture of Compound A (3.0 g, 15.1 mmol) in THF (75 mL) was added a solution of nBuLi in hexane (2.5 M, 6.4 mL, 15.1 mmol). After 15 min, DMF (1.4 mL, 18.1 mmol) was added and the mixture was stirred for 3 h followed by addition of saturated aqueous NH4CI (30 mL).
The mixture was extracted with ethyl acetate and the organic phase was washed with saturated aqueous NH4CI, brine, dried using MgSO4, filtered and concentrated to yield 3.1g of Compound B (92%) as a light yellow oil. MS (2M+H)+ 453.2 C . 1-Amino-1 -[N-[2-(trimethylsilyl)ethoxymethyl]imidazoI-2- yl]-but-3-ene
To a cooled (-78°C) mixture of Compound B (1.22g, 5.4 mmol) in THF (10 mL) under Ar was added via syringe a precooled (-78°C) solution of lithium bistrimethylsilylamide in THF (1 M, 5.6 mL, 5.6 mmol). The mixture was warmed to -20°C for 1 h and recooled to -78°C. To the mixture was added via syringe a precooled (-78°C) solution of allylmagnesium bromide (1 M in ethyl ether, 7.45 mL, 7.45 mmol). The mixture was warmed to room temperature and stirred for 16 h under Ar. The mixture was quenched with 1 N aqueous NaOH (20 mL) and extracted with ethyl ether. The organic layer was washed with brine, dried using MgSO4, filtered and concentrated to a yellow residue. The residue was chromatographed on a flash silica gel column (5x20 cm) eluting with methylene chloride:methanol (9:1) followed by ammonium hydroxide:methanot:chloroform (1 :5:94) to yield 0.55 g (38%) of Compound C an orange liquid. MS (M+H)+ 267.
D . 1 -[(Triethylsilyl)ethoxycarbonylamino]-1-[N-[2- (trimethylsilyl)ethoxymethyl]imidazol-2-yl]-but-3-ene
To a stirred suspension of Compound C (450 mg, 1.7 mmol) in water (2 mL) was added a solution of TEA (0.32 mL, 2.3 mmol) in dioxane (2 mL) followed by 2-(triethylsilyl)ethoxycarbonylsuccinimide. The mixture was stirred at room temperature for 16 h. Ethyl ether (30 mL) and 1 N aqueous KHSO4
(30mL) were added. The layers were separated and the aqueous layer was washed with ethyl ether. The pooled organic layers were dried using MgSθ4, filtered and concentrated. The residue was chromatographed on a flash silica gel column (5x20 cm) eluting with methylene chloride:methanol (9:1) to yield 531 mg (84%) of Compound D as a glass. MS (M+H)+ 412.
E. 3-[(Triethylsilyl)ethoxycarbonylamino]-3-[N-[2- (trimethylsilyl)ethoxymethyl]imidazol-2-yl]-propanal
To a stirred mixture of Compound D in dioxane (5 mL) and water (5 mL) was added sodium periodate (94 mg, 0.37 mmol) and osmium tetroxide (2 mg dissolved in 0.5 mL water, 0.5 mL dioxane). The mixture was stirred for 18 h. Methylene chloride was added, the layers were separated and the aqueous layer was washed with methylene chloride. The combined organic layers were dried using MgSO4, filtered and concentrated. The residue was chromatographed on a flash silica gel column (5x20 cm) eluting with methylene chloride:methanol (9:1) to yield 90 mg (90%) of Compound E as a glass.
F. 1 -[[(Triethylsilyl)ethoxycarbonylamino]-3-(1- (trimethylsilyl)ethoxymethyl-imidazol-2-yl)propyl]-2, 3,4,5- tetrahydro-4-(1-naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine
Compound F was prepared from Compound E and Compound C of Example 1 as described for Compound D of Example 1 , with stirring for 16 hours. Chromatography (flash, silica, 9:1 methylene chloride:methanol) afforded (44%) of Compound F as a glass. MS (M+H)+ 700.
G. 1 -[3-Amino-3-(1 H-imidazol-2-yl)propyl]-2,3,4,5- tetrahydro-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride To a solution of Compound F (20 mg, 0.029 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (44 mg, 0.17 mmol) and the solution was heated to 50°C for 16 h. On cooling, the solvent was removed under vacuum and the residue was dissolved in a 50/50 mixture of 0.1%TFA in methanol and 0.1%TFA in water and applied to a YMC C18 column (S-5, ODS 30x250 mm). HPLC purification was performed under the following conditions; Solvent A; 0.1%TFA in 90% water, 10% methanol, Solvent B; 0.1%TFA in 90% methanol, 10% water; 0-100%B in A over 30 minutes. Fractions containing the major peak were pooled and lyophilized to an oily residue. 1 M aqueous HCl (6 mL) was added and the solution was concentrated to a white solid. This step was repeated to give 9 mg (58%) of Example 15 as a white solid. MS (M+H)+ 425 1 H-NMR (CD3OD, 270 MHz) d 8.05-7.95 (2H, m), 7.7-7.05 (10H, m), 6.71
(0.5H, m), 6.02(0.5H, m), 4.4 (2H, m), 4.0 (1 H,m), 3.6-3.0 (7H, m), 2.9 (1 H, m).
Example 16
Figure imgf000062_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-methyl-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 16 was prepared as a yellow solid from isatoic anhydride and D,L- alanine ethyl ester hydrochloride as described for Example 8, mp 180- 185°C.
MS (M+H)+ 397
Analysis calculated for C25H24N4O «1.3 HCl *1.3 H2O.
Calc'd: C, 64.26; H, 6.02; N, 11.99; Cl, 9.86. Found: C, 64.33; H, 5.82; N, 11.70; Cl, 9.65.
Example 17
Figure imgf000062_0002
(S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[2- (methylthio)ethyl]-4-(1-naphthalenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
To a suspension of ethylene glycol dimethyl ether (anhydrous, 20 mL) and lithium aluminum hydride (17 mg, 0.45 mmol) under argon at 0° C was slowly added a mixture of Example 8 (75 mg, 0.15 mmol) in ethylene glycol dimethyl ether. The mixture was allowed to warm to room temperature, stirred for 30 min. and heated to reflux (85°C) for 18 hours. The mixture was cooled to 0°C and quenched sequentially with a mixture of tetrahydrofuran and water (1 mL each), aqueous sodium hydroxide, (2 mL, 1 N) and water (1 mL). The resultant precipitate was removed by filtration and the filtrate was concentrated in vacuo to yield an amber oil. This material was dissolved in methanol (2 mL), treated with a solution of hydrogen chloride (1 mL, anhydrous, 2M in ether), and concentrated in vacuo to yield Example 17 as a yellow solid, mp 115-120 °C.
MS (M+H)+ 443
Analysis calculated for C27H30N4S »2.4 HCl »2.6 H2O. Calc'd: C, 56.21 ; H, 6.57; N, 9.71 ; Cl, 14.75. Found: C, 56.20; H, 6.55; N, 9.85; Cl, 14.81.
Example 18
Figure imgf000063_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-9-methy l-4-(1 - naphthaienylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 18 was prepared as a light yellow solid from 8-methyl isatoic anhydride and glycine ethyl ester hydrochloride as described in the following multistep sequence: Compound A of Example 1 , with refluxing for 16 hours; Example 17, except that THF was used as solvent; refluxing with the 4-nitrophenyl ester of 1-naphthoic acid in toluene in the presence of DMAP; Compound D of Example 1. MS (M+H)+ 397 Analysis calculated for C25H24N4O «2 HCl.
Calc'd: C, 63.96; H, 5.58; N, 11.93. Found: C, 62.83; H, 5.77; N, 11.13. Example 19
Figure imgf000064_0001
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-9-methyl-1 -(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 19 was prepared from 9-methyl-2,3,4,5-tetrahydro-1 ,4- benzodiazepine as described in the following multistep sequence: Compound A of Example 4; coupling with 1 -naphthoyl chloride using triethylamine in methylene chloride; Boc removal with 4N HCl in dioxane; Compound D of Example 1 ; chromatography (silica, flash, 9/1 CHCI3/CH3OH) followed by treatment with 1M HCl in ether and trituration with ether afford Example 19 as a light yellow solid.. MS (M+H)+ 397
1 H NMR (270 MHz, CD3OD) d 9.12 -8.9 (m, 1 H), 8.5-8.23 (m, 1 H), 8.1-7.9
(m, 3H), 7.9-7.0 (m, 7 H), 57-5.28 (m, 1H), 4.85-4.1 (m, 3H), 4.0-3.05 (m, 4 H), 2.9-2.55 m, 1H), 1.9-1.75 (s, 3H).
Example 20
Figure imgf000064_0002
1 -[[2-(2-Aminoethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro- 4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride. A. [2-(2-[[(1 ,1 -dimethyl)-ethoxycarbonyl]amino]ethyl)-1 - [(1 ,1-dimethyi)-ethoxycarbonyl]-imidazol-4-yl]methanol
[2-(2-Aminoethyl)-1 H-imidazol-4-yl]methanol hydrochloride was prepared as described (Buschauer, et. al., Arch. Pharm., 315, 563, (1982)). To a suspension of 1.0 g of this crude material (assumed 4.7 mmol) in 10 mL of DMF was added 2 mL (14.1 mmol) of triethylamine and the slurry was stirred for 0.5 hr. To the reaction was then added 3.1 g (14.1 mmol) of BOC anhydride and stirring was continued overnight at rt. The reaction was evaporated to dryness and the residue subjected to flash chromatography on a 100 cc column of silica gel. Elution with ethyl acetate afforded 1.27 g (3.7 mmoles, 79 %) of Compound A as a viscous yellow oil.
B. [2-(2-[[(1 ,1-dimethyl)-ethoxycarbonyl]amino]ethyl)-1 - [(1 ,1-dimethyl)-ethoxycarbonyl]-imidazol-4-yl]carboxaldehyde To a solution of 1.2 g (3.5 mmol) of Compound A in 10 mL of chloroform was added 0.9 g (10 mmol) of manganese dioxide. The reaction was heated at 50° C with vigorous stirring. Additional 0.3 g portions of Mnθ2 were added after 1 , 2 and 4 hrs of heating. After 6 hr at 50° C, the mixture was cooled to room temperature and without workup, was subjected to flash chromatography on a 150 cc column of silica gel. Elution with 50 % ethyl acetate-hexane afforded 673 mg (57 %) of Compound B as a white crystalline solid.
C . 1-[[2-(2-Aminoethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5- tetrahydro-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride
Compound C of Example 1 was reductively aminated with Compound B as described for Compound D of Example 1. The resulting oil was subjected to flash chromatography (silica, 50 % ethyl acetate-hexanes) to afford the bis- Boc analog of Compound C as a white foam. A solution of 94 mg (0.15 mmol) of this material in 3 ml of 4 N. HCI-dioxane was stirred for 3 hr at rt. Removal of solvent gave a white foam residue which was subjected to preparative HPLC on a YMC S5 ODS (30 x 250 mm) column. Gradient elution from 0 to 100% solvent B (A: 10% methanol:water + 0.1% TFA, B: 10% wateπmethanol + 0.1 % TFA) afforded an oil residue which was converted to its HCl salt by the addition of methanolic HCl and removal of solvent. The residue was evaporated from methanol twice more to afford 53 mg (0.10 mmole, 66%) of Example 20 as a white solid, mp 165°C.
MS (M+H)+ 426
Analysis calculated for C26H27N5O »3 HCl. Calc'd: C, 58.38; H, 5.65; N, 13.09. Found: C, 59.01; H, 6.15; N, 13.03.
Example 21
Figure imgf000066_0001
1 -[[2-(2-Aminomethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5- tetrahydro-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 21 was prepared as a white solid from chloroacetonitrile and Compound C of Example 1 as described for Example 20, mp 155-160°C. MS (M+H)+ 412 Analysis calculated for C25H25N5O »3 HCl. Calc'd: C, 57.65; H, 5.42; N, 13.45. Found: C, 57.41 ; H, 5.18; N, 13.17.
Example 22
Figure imgf000067_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-ylJacetamide, dihydrochloride.
A. 2-[2-[[(1 ,1 -Dimethyl)-ethoxycarbonyl]amino]ethylamino]- 4-nitro-benzoic acid
Sodium cyanoborohydride (2.3 g, 38 mmol) was added portionwise to a solution of 2-[[(1 ,1-dimethyl)-ethoxycarbonyl]amino]acetaldehyde (6.0 g, 38 mmol), 4-nitroanthranilic acid (3.8 g, 19 mmol) and acetic acid (2.0 ml) in methanol (150 ml). The mixture was stirred at room temperature for 16h, concentrated under vacuum, quenched with 1 N HCl (100 ml) and extracted with CH2CI2 (3x100 ml). The combined organic extracts were dried (MgSθ4), filtered and concentrated under vacuum. The residue was purified by flash chromatogrphy (19 / 1 / 0.05 CHCI3 / MeOH / AcOH ) to afford Compound A (4.4 g, 72%) as a solid. MS: (M+H)+ 326
B. 2-[(2-amino)ethylamino]-4-nitro-benzoic acid
Anhydrous HCl in dioxane (4M, 20 ml, 80 mmol) was added to Compound B (2.8 g, 8.6 mmol) at room temperature and the mixture was stirred for 2h. The solution was concentrated under vacuum and the residue was triturated with diethyl ether to afford Compound B (2.1 g, 84%) as a solid. MS: (M+H)+ 226
C . 8-Nitro-2,3,-dihydro-1 H-1 ,4-benzodiazepin-5-one
Diphenylphosphoryl azide (1.1 ml, 5.0 mmol) was added to a solution of Compound B (1.0 g, 3.4 mmol) in DMF (12 ml) at room temperature. The mixture was stirred for 10 minutes, N-methyl morpholine (1.3 ml, 12 mmol) was added and the mixture was stirred at room temperature for 5h. The mixture was quenched with 10% LiCI /10% NaHCO3 (100 ml) and the aqueous solution extracted with ethyl acetate (5X50 ml). The combined organic extracts were washed with 10% LiCI (2X60 ml), dried (MgS04), filtered and concentrated under vacuum. The residue was triturated with petroleum ether and diethyl ether to afford Compound C (0.42 g, 61 %) as a solid. MS: (M+CH3CN+H)+ 249
D . 8-Nitro-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine Borane dimethyl sulfide (10 M, 1.2 ml, 12 mmol) was added dropwise to solution of Compound C (0.42 g, 2.0 mmol) in THF (5 ml) at 0°C. The mixture was warmed to room temperature and then heated to refluxed for 2h. The mixture was cooled to 0°C, methanol (10 ml) was carefully added and the solution was saturated with anhydrous HCl. The mixture was heated to reflux for 1 h, concentrated under vacuum and triturated with diethyl ether to afford Compound D (0.34 g, 65%) as a solid. MS: (M+H)+ 194
E . 8-Nitro-2,3,4,5-tetrahydro-4-(1 -naphthalenylcarbony I)- 1 H-1 ,4-benzodiazepine Compound E was prepared from Compound D and 1-naphthoyl chloride as described for Compound C of Example 2, with stirring for 16 hours. MS: (M+CH3CN+H)+ 389
F. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-8-nitro-1 H-1 ,4-benzodiazepine
Compound F was prepared from Compound E as described for Compound D of Example 1 , except that methanol was used as solvent and the free base was carried on to the next reaction. MS (M+H)+ 428
G. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalβnylcarbonyl)-8-amino-1 H-1 ,4-benzodiazepine
Iron powder (0.15 g, 2.6 mmol) was added to a solution of Compound F (0.13 g, 0.29 mmol) in 500/50/1 ethanol / water / concentrated HCl (26 ml) at room temperature. The mixture was heated to reflux for 3h, cooled to room temperature, filtered and the filtrate was concentrated under vacuum. The residue was dissolved in CH2CI2 (100 ml), washed with 1 N NaOH (100 ml), and the aqueous layer reextracted with CH2CI2 (2X100 ml). The combined organic extracts were dried (MgS04), filtered and concentrated under vacuum to afford Compound G (0.60 g, 52%) as a solid which was used without further purification.
H . N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]acetamide, dihydrochloride
4-Dimethylaminopyridine (0.005 g) was added to a solution of Compound G (0.050 g, 0.13 mmol) and acetic anhydride (0.024 ml, 0.25 mmol) in CH2CI2 (2 ml) at room temperature. The mixture was stirred for 16h, quenched with 10% NaHCO3 (1 ml) and MeOH (0.50 ml) and stirred at room temperature for 15 minutes. The mixture was diluted with water (5 ml) and the solution extracted with CH2CI2 (3X50 ml). The combined organic extracts were dried (MgSθ4), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19 / 1 / 0.01 CHCI3 / MeOH / NH4OH) and the appropriate fractions were concentrated under vacuum. The residue was dissolved in MeOH (5 ml), treated with 1N HCl (2 ml), millpore filtered and lyophilized to afford Example 22 (0.018 g, 32% ) as a solid. MS (M+H)+ 440 Analysis calculated for C26H25N5O2 «2.0 HCl «1.16 CH3OH.
Calc'd: C, 59.35; H, 5.80; N, 12.74 Found: C, 59.35; H, 5.81 ; N, 12.22.
Example 23
Figure imgf000069_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-pyrido[2,3-e]-1 ,4-diazepine, trihydrochloride.
A. 2,3,4,5-Tetrahydro-1 H-pyrido[2,3-e]-1 ,4-diazepin-5-one A solution of 2-chloronicotinamide (4.0 g, 25.5 mmol) in ethylenediamine (25 mL) was heated to reflux for 24 hours. To the solution was added 5 N NaOH (5.1 mL, 25.5 mmol) and the mixture was concentrated in vacuo. The crude material was chromatographed (silica, 5-20% CH3OH/CHCI3) to give Compound A (339 mg, 8%) as a light yellow solid. MS (M+H+CH3CN)+ 205.
B. 2,3,4,5-Tetrahydro-1 H-pyrido[2,3-e]-1 ,4-diazepine
To a solution of Compound A (100 mg, 0.61 mmol) in dry toluene (15 mL) was added diisobutylaluminum hydride (1M in hexanes, 3.1 mL, 3.1 mmol). The mixture was warmed to reflux for 36 hours. At 12 and 24 hours, an additional portion of DiBAH was added (3.1 mL each time). At the end of 36 hours, the reaction was cooled to room temperature and quenched with methanol. A viscous gel was formed which was dissolved in 1 N HCl. The mixture was extracted with EtOAc (15 mL) and the organic layer discarded. The aqueous layer was made basic with 5N NaOH and extracted with 10% /- PrOH/CH2Cl2 (5x15 mL). The organic layers were combined, dried over Na2Sθ4, and concentrated in vacuo to afford Compound B (79 mg, 87%) which was carried on directly. MS (M+H+CH3CN)+ 191.
C . 2,3,4,5-Tetrahydro-4-(1 -naphthalenylcarbonyl)-1 H- pyrido[2,3-e]-1 ,4-diazepine
To a solution of Compound B (79 mg, 0.53 mmol), 1 -naphthoic acid (115.5 mg, 0.67 mmol), EDC (128.4 mg, 0.67 mmol), and HOBt (90.5 mg, 0.67 mmol) in anhydrous DMF (2 mL) was added diisopropylethylamine (0.1 mL, 0.67 mmol). After 3 hours, the reaction was diluted with EtOAc (5 mL) and washed with 10% LiCI. The organic layer was washed with 1 N HCl and discarded. The aqueous layer was made basic with 5N NaOH and extracted with EtOAc (5x5 mL). The five organic layers were combined and dried over Na2Sθ4 and concentrated. The crude material was chromatographed (silica, 0-5% CH3OH/CHCI3) to give Compound C (96 mg, 60%) as a light brown oil. MS (M+H+CH3CN)+ 345. D . 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-pyrido[2,3-e]-1 ,4-diazepine, trihydrochloride
To a solution of Compound C (30 mg, 0.10 mmol) and 4-formyl imidazole (14.5 mg, 0.50 mmol) in dichloroethane (0.5 mL) and acetic acid (0.25 mL) was added NaBH(OAc)3 (29.7 mg, 0.14 mmol). The mixture was stirred at room temperature for 12 hours and at 80°C for 12 hours. Additional portions of 4-formyl imidazole (14.5 mg, 0.50 mmol) and NaBH(OAc)3 (30 mg, 0.14 mmol) were added and the reaction was warmed to 80°C for an additional 24 hours. The reaction was cooled to room temperature and diluted with EtOAc (2 mL) and NH4OH (cone, 2 mL) was added. After stirring for 3 hours, NaHCθ3 (sat., 3 mL) was added along with more EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The organic layers were combined and washed with NH4CI (sat., 5 mL), dried over Na2Sθ4, and concentrated in vacuo. The crude material was diluted in methanol (2 mL) and purified by HPLC (YMC S5 ODS 30X250 mm column, solvent A: 10% MeOH/H2θ w/ 0.1% TFA, solvent B: 90% MeOH/H2θ w/ 0.1% TFA, gradient: 0-100%B in A over 60 min at a rate of 25 mLΛnin, monitored at 220 nm). The fractions containing the product were combined, concentrated in vacuo, dissolved in 1N HCl and lyophilized, dissolved in water and lyophilized again to give Example 23 as a fluffy white solid (4 mg, 8%). 1 H-NMR (CD3OD, 400 MHz) d 8.87 (d, Ji = 1.3, 0.5H), 8.70 (d, Ji = 1.3, 0.5H), 8.06 (dd, Ji = 1.7, J2 = 5.6, 0.5H), 7.96 (d, Ji = 6.8, 0.5H), 7.83-7.91 (m, 2.5H) 7.60 (d, Ji = 1.3, 0.5H), 7.52 (dd, Ji = 1.7, J2 = 7.3, 0.5H), 7.34-7.49 (m, 4H), 7.26 (dd, Ji = 1.3, J2 = 7.6, 0.5H), 7.11 (dd, Ji = 1.3, J2 = 7.1 , 0.5H), 7.05 (dd, Ji = 5.6, J2 = 7.3, 0.5H), 6.57 (d, Ji = 7.3, 0.5H), 6.52 (dd, Ji = 5.6, J2 = 7.7, 0.5H), 5.01 (d, Ji = 1.3, 1H), 4.95 (d, Ji = 1.3, 1 H), 4.39-4.57 (m, 1.5H), 4.08-4.13 (m, 1H), 3.88-3.94 (m, 1 H), 3.53-3.65 (m, 1.5H), 3.42-3.45 (m, 1H); MS (M+H)+ 384.
Example 24
Figure imgf000072_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-naphtho[2,3-e]-1 ,4-diazepine, dihydrochloride.
A. 2H-3,1 -Naphthoxazine-2,4(1 H)-dione To an ice cooled slurry of 25 g (10.7 mmol) of 80% 2-amino-3-naphthoic acid and 2.5 g (8.5 mmol) of triphosgene in 70 mL of acetonitrile, under argon, was added dropwise 0.35 mL (25 mmol) of.triethylamine. Stirring was continued while the cooling bath was allowed to warm to room temperature and then overnight at room temperature. To the resulting suspension was then added 2 mL of methanol and stirring was continued for an additional hour. Filtration of the solid afforded 2.5 g (assumed 100 %) of crude Compound A as a light brown powder.
B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-naphtho[2,3-e]-1 ,4-diazepine, dihydrochloride
Example 24 was prepared as an amorphous off-white solid from Compound A by the following mulitstep sequence: Compound A of Example 1 , with refluxing for 10 hours; Compound B of Example 2, except that THf was used as solvent and the produc borane complex was decomposed with refluxing aqueous HCl; Compound C of Example 2, except that chromatography was done with 50% ethyl acetate-hexane afforded; Compound D of Example 1 , with the product purified by prep HPLC (YMC S5 ODS (30x250 mm) column, gradient elution from 40 to 100% solvent B (A: 10% methanol:water + 0.1% TFA, B: 10% wateπmethanol + 0.1 % TFA) and converted to the HCl salt by treatment with HCI-MeOH. Analysis calculated for C28H24N4O «1.5 HCl »0.25 H2O. Calc'd: C, 68.39; H, 5.33; N, 11.39. Found: C, 68.41 ; H, 5.46; N, 11.31.
Example 25
Figure imgf000073_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-8-nitro-1 H-1 ,4-benzodiazepine, dihydrochloride.
Sodium triacetoxyborohydride (0.91 g, 4.3 mmol) was added to a solution of Compound E of Example 22 (0.50 g, 1.43 mmol), 4-formyl imidazole (0.41 g, 4.3 mmol) and AcOH (4 mL) in CH2CI2 (4 mL). After stirring for 15 hr, the mixture was diluted with CH2CI2 (10 mL), NH4OH (5 mL) and NaHCO3 (5 mL), and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The product was purified over silica gel column eluting with 19/1 CHCI3/CH3OH to afford Example 25 (0.52 g, 85 %) as a light yellow solid. (Example 25 is also Compound F of Example 22.) MS (M+H)+ 428.
Example 26
Figure imgf000074_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-8-amino-1 H-1 ,4-benzodiazepine, dihydrochloride.
16 % aqueous TiCl3 (2 mL) was added to a solution of Example 25 (0.10 g, 0.23 mmol) in AcOH/H2θ (2 mL, 1 :1). After stirring for 15 min, the reaction was made basic with 1 N NaOH and NaHCO3 and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 CH3OH (9 / 1). The combined organic layers were dried over MgSθ4, filtered and concentrated to afford 0.92 g. (73 %) of Example 26. A 20 mg. sample of this material was treated with 1 M HCl in ether (2 mL). A light yellow solid was formed which was triturated several times with ether and dried under vacuum to afford Example 26 (23 mg. ) as a light yellow solid. (Example 26 is also Compound G of Example 22.) MS (M+H)+ 398.
Example 27
Figure imgf000075_0001
N-[2,3,4,5-Tetrahydro-1-{1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]benzamide, dihydrochloride.
Benzoyl chloride (0.016 g, 0.013 mL) was added to a solution of Example 26 (0.042 g, 0.10 mmol) in CH2CI2 (1 mL) and triethyl amine (0.01 g, 0.016 mL) at 0°C. After stirring for 2 hr, the mixture was diluted with NaHCO3 (2 mL) and CHCI3 (10 mL). The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgSθ4, filtered and concentrated. The residue was purified on a silica flash column eluting with CH3CI/CH3OH (9 / 1). The product was treated with 1M HCl in ether (2 mL). A light yellow solid was formed which was triturated several times with ether and dried under vacuum to afford Example 27 as a light yellow solid (0.015 g, 28%). MS (M+H)+ 502. IR: (KBr): 3434, 2930,1611 ,1508, 1424, 1263 cm"1.
Example 28
Figure imgf000076_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8- yljcyclohexanamide, dihydrochloride.
Example 28 was prepared from Example 26 and cyclohexanecarbonyl chloride as described for Example 27. The crude product was directly treated with HCl / ether. The yellow solid which formed was triturated with ether several times and dried under vacuum to afford Example 28 as a yellow solid in 90% yield.
MS (M+H)+ 508.
IR: (KBr): 3434, 2930,1611,1508, 1424, 1263 cm"1.
Example 29
Figure imgf000077_0001
2,3,4,5-Tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethyl]-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 2,3,4,5-Tetrahydro-1-[1-oxo-2-(1-triphenylmethyl- imidazol-4-yl)ethyl]-4-[(1 ,1 -dimethylethoxy)-carbonyl]-1 H-1 ,4- benzodiazepine
To a solution of 250 mg (0.68 mmol) of N-triphenylmethyl-4-imidazole acetic acid and 94 μl (0.68 mmol) of triethylamine in 3 mL of THF at -30°C under argon was added dropwise 97 μl (0.75 mmol) of isobutylchloroformate. Stirring was continued for 10 min and a solution of 253 mg (1.02 mmol) of Compound A of Example 4 in 1 mL of THF was added. The mixture was stirred 7 hours as it warmed to room temperature and diluted with ethyl acetate. The solution was washed with brine, saturated NaHCO3 and brine, dried (MgS04) and concentrated. The resulting oil was subjected to flash chromatography (silica gel, 75 % ethyl acetate:hexanes) to afford 195 mg (0.33 mmol, 48%) of Compound A as a white foamy solid.
B. 2,3,4,5-Tetrahydro-1-[2-(1 H-imidazol-4-yl)ethyl]-4-[(1 ,1- dimethylethoxy)-carbonyl]-1 H-1 ,4-benzodiazepine
To a solution of 100 mg (0.17 mmol) of Compound A in 1 mL of THF under argon was added 1 mL (1 mmol) of 1 M borane in THF. After the initial foaming had ceased, the mixture was heated at 60°C for 1 hour and cooled to room temperature. Cone. HCl (0.5 mL) was added and the solution was heated at 60°C for 1 hour and evaporated to dryness. The residue was diluted with water and the solution was washed twice with ethyl acetate, rendered alkaline by the dropwise addition of 40% KOH-water, and extracted with methylene chloride (3x). The combined methylene chloride extracts were washed with brine (2x), dried (MgS04), and the solvent removed to give 39 mg of viscous oil. This material was subjected to flash chromatography (silica gel, CHCl3:MeOH:NH4OH 80:20:2) to afford 16 mg (0.066 mmol, 40%) of Compound B as an oil
C . 2,3,4,5-Tetrahydro-1-[2-(1 H-imidazol-4-yl)ethyl]-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Compound C was prepared from Compound B (30 mg, 0.12 mmol) as described for Compound C of Example 23 with stirring for 18 hours. The mixture was evaporated to dryness and the residue subjected to flash chromatography (silica gel, 10% methanokchloroform) to afford 33 mg of material which was subjected to prep HPLC on a YMC S5 ODS (30x250 mm) column. Gradient elution from 30 to 100% solvent B (A: 10% methanokwater + 0.1 % TFA, B: 10% watermethanol + 0.1% TFA) afforded a clear glass residue which was converted to the HCl salt by treatment with HCI-MeOH to give 20 mg (0.04 mmol, 36%) of Example 29 as a solid foam. MS (M+H)+ 397
Analysis calculated for C25H24N4O «2 HCl »1.5 H2O
Calc'd: C, 60.48 H, 5.89; N, 11.28. Found: C, 60.69 H, 5.63; N, 11.12.
Figure imgf000078_0001
2,3,4,5-Tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethyl]-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride. A. 2,3,4,5-tetrahydro-4-[(1 ,1 -dimethylethoxy)-carbonyl]-7- phenyl-1 H-1 ,4-benzodiazepine
Di-tert-butyl dicarbonate (6.1 g, 28 mmol) was added to a solution of Compound B of Example 12 (5.2 g, 23 mmol) in THF (50 mL). The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by flash chromatography (silica, ethyl acetate) to afford Compound A (5.7 gm, 91 %) as an oil. MS: (M+H)+ 325
B. 2,3,4,5-Tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethylj-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride
Example 30 was prepared from Compound A by the following 3 step procedure: Compound A of Example 29; Compound B of Example 29, with refluxing for 4 hours and quenching of excess borane by the dropwise addition of methanol; Compound B of Example 3, with stirring at room temperature for 2 hours and flash chromatography on silica with 10% methanol/chloroform followed by preparative HPLC (YMC S5 ODS (30x250 mm) column; gradient elution from 40 to 100% solvent B (A: 10% methanokwater + 0.1% TFA, B: 10% watermethanol + 0.1% TFA); the clear glassy residue which was converted to the HCl salt by treatment with HCI- MeOH to give Example 30 as a foamy solid. MS (M+H)+ 473 Analysis calculated for C31 H28N4O «2.15 HCl »1 H2O
Calc'd: C, 65.44 H, 5.69; N, 9.85 Found: C, 65.56 H, 5.26; N, 9.40.
Example 31
Figure imgf000080_0001
7-Bromo-2,3,4,5-tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethyl]-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 31 was prepared from 7-bromo-1 ,4-benzodiazepine (prepared as described in Compound B of Example 11 ) by the following procedure: Compound A of Example 4; Compound A of Example 29 with stirring for 2 hours and chromatography in ethyl acetate; Compound B of Example 29, with the borane reduction refluxed for 3 hours, the HCl treatment at 60°C for 2 hours, and chromatography with chloroform:methanol:NH4θH (90:10:1);
Compound C of Example 23, with silica gel chromatography using 20% methanokchloroform and preparative HPLC using a 40-100% B gradient. MS (M+H)+ 475 Analysis calculated for C25H23N4θBr -2 HCl -0.35 H2O
Calc'd: C, 55.41 H, 4.67; N, 9.79. Found: C, 55.55 H, 4.53; N, 10.00.
Example 32
Figure imgf000081_0001
1 -[[1-(2-Aminoethyl)-1 H-imidazol-5-yl]methyl]-2,3,4,5-tetrahydro- 4-(1 -naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride.
A- 1 -[["• -[(1 ,1 -dimethylethoxy)-carbonyl]-1 H-imidazol-4- yl]methyl]-2,3,4,5-tetrahydro-4-(1 -naphthalenylcarbonyl)-7- phenyl-1 H-1 ,4-benzodiazepine
A solution of 150 mg (0.33 mmol) of Example 12, 144 mg (0.66 mmol) of di-t-butyldicarbonate, and 5 mg of dimethylaminopyridine in 2 mL of methylene chloride was stirred overnight under argon. The mixture, without workup, was subjected to flash chromatography (silica gel, 50 % ethyl acetate-hexanes) afforded 142 mg (0.25 mmol, 77 %) of Compound A as a white foamy solid.
B. 1 -[[1-(2-(N-phthalimidoethyl)-1 H-imidazol-5-yl]methyl]- 2,3,4,5-tetrahydro-4-(1 -naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4- benzodiazepine
To an ice cooled solution, under argon, of 0.5 g (2.6 mmol) of N- hydroxyethyl-phthalimide and 315 μL (3.9 mmol) of pyridine in 5 mL of methylene chloride was added dropwise a solution of 527 μL (3.1 mmol) of triflic anhydride in 5 mL of methylene chloride. Stirring was continued with cooling for 0.5 hours, and at room temperature for 1 hour. A voluminous precipitate was obtained. The reaction was hydrolyzed by the addition of ice and stirred 10 minutes. The organic layer was washed with 5% NaHSθ4 and brine, dried (MgSθ4), and the solvent removed to afford 615 mg (1.9 mmol, 73%) of the trifiate as a white solid. A solution of 44 mg (0.13 mmol) of this trifiate and 75 mg (0.13 mmol) of Compound A in 1.5 mL of methylene chloride was stirred overnight under argon. The mixture, without workup, was subjected to flash chromatography (silica gel, ethyl acetate, followed by 10% methanol-chloroform) to afford 41 mg (0.065 mmol, 50 %) of Compound B as a white foamy solid.
C . 1 -[[1 -(2-Aminoethyl)-1 H-imidazol-5-yl]methyl]-2,3,4,5- tetrahydro-4-(1 -naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4- benzodiazepine, trihydrochloride. A solution of 60 mg (0.095 mmol) of Compound C and 100 μL of hydrazine in 0.5 mL of methanol was stirred overnight under argon. The resulting precipitate was removed by filtration and the clear, colorless filtrate subjected to prep HPLC on a YMC S5 ODS (30x250 mm) column. Gradient elution from 25 to 100% solvent B (A: 10% methanol: water + 0.1 % TFA, B: 10% water:methanol + 0.1 % TFA) afforded a white solid which was converted to the HCl salt by treatment with HCI-MeOH to give 11 mg (0.18 mmol, 19 %) of Example 32 as an amorphous pale-yellow solid.
MS (M+H)+ 502
1H NMR (270 MHz, CD3OD, as a mixture of rotamers/conformers): d 3.00 (1 H, m), 3.43 (2H, m), 3.57 (2H, m), 4.09 (1 H, m), 4.20 (1 H, m), 4.50 (1 H, m), 4.59 (1 H, m), 4.72 (2H, m), 5.02 (1 H, m), 6.09 (1 H, s), 7.03 (1 H, m), 7.22-8.05 (13H, m), 9.12 and 9.18 (1H, m). IR (KBr): 764 cm"1 , 781 , 1144, 1487, 1510, 1609, 2924, 3418.
Example 33
Figure imgf000082_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine-4-carboxylic acid, phenylmethyl ester. A. 2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 ,1 - dimethylethoxy)-carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine
Sodium triacetoxyborohydride (4.5 g, 21 mmol) was added to a solution of Compound A of Example 30 (4.6 g, 14 mmol) and 4-formylimidazole (2.7 g, 28 mmol) in 1:1 methylene chloride/ AcOH (40 mL) at room temperature. The mixture was stirred at room temperature for 16 hours and concentrated under vacuum. The residue was dissolved in methylene chloride (100 mL) and 1/1 1 N NaOH/ NH4OH (100 mL) and the mixture was stirred at room temperature for 16 hours. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3X50 mL). The combined organic extracts were dried (MgSθ4), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19/1 CHCI3/MΘOH) to afford Compound A (5.7 g, 100%) as a solid. MS: (M+H)+
405
B. 2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl- 1 H-1 ,4-benzodiazepine
Anhydrous HCl (4M, 20 mL, 80 mmol) in dioxane was added to Compound A (2.0 g, 5.0 mmol). The mixture was stirred at room temperature for 4 hours and concentrated under vacuum. The residue was dissolved in water (10 mL) and 1 N NaOH (15 mL) was added. The solution was extracted with methylene chloride (4x75 mL) and the combined organic extracts were dried (MgS04), filtered and concentrated under vacuum to afford Compound B
(1.45 g, 97%) as a solid. MS: (M+H)+ 305
C . 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl- 1 H-1 ,4-benzodiazepine-4-carboxylic acid, phenylmethyl ester p-Nitrophenylbenzylcarbonate (0.04 g, 0.16 mmol) was added to a solution of Compound B (0.2 M, 1.0 ml, 0.16 mmol) in DMF. The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (50 mL) and washed with 10% LiCI (50 mL). The aqueous layer was reextracted with ethyl acetate (2x50 mL). The organic fractions were combined, washed with 10% LiCI (2x50 mL), dried (MgS04), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19/1/0.05 CHCl3/MeOH/AcOH) to afford Example 33 (0.07 g, 93%) as a white solid.
MS (M+H)+ 439.
Analysis calculated for C27H26N4O2 "0.05 H O. Calc'd: C, 72.52; H, 6.08; N, 12.53. Found: C, 72.51 ; H, 5.85; N, 12.47.
Example 34
Figure imgf000084_0001
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[2- (trif luoromethoxy)benzoyl]-1 H-1 ,4-benzodiazepine.
A solution of HOAt (0.014 gm, 0.10 mmol) in DMF (0.5 mL) was added to o- trifluoromethoxybenzoic acid (0.021 g, 0.10 mmol) at room temperature. A DMF solution of Compound B of Example 33 (0.2 M, 0.50 ml, 0.16 mmol) and diisopropyl carbodiimide (DIC, 0.013 ml, 0.10 mmol, 1.0 equiv) were added to the mixture, which was stirred at room temperature for 16 hours. The mixture was purified by ion exchange chromatography on a solid phase extraction cartridge using the following protocol:
1) Conditioned a Varian solid phase extraction column (1.5 g, SCX cation exchange) with 10 mL of MeOH/CH2Cl2 2) Loaded mixture onto column using a 10 mL syringe to pressurize the system
3) Wash column with 3 X 7.5 mL MeOH/CH2Cl2 (1 :1)
4) Wash the column with 1 X 7.5 mL of 0.01 N ammonia in MeOH
5) Eluted column with 7.5 mL of 1.0 N ammonia in MeOH and collect into a tared receiving tube.
The solution containing product was concentrated on a Savant Speed Vac (approx. 2mm Hg for 20 hours). The residue was dissolved in CH3CN (1 mL) and water (1 mL) and lyophilized to afford Example 34 (0.42 gm, 85%) as a white lyophilate. MS: (M+H)+ 493
Analysis calculated for C27H23N4O2F3 »0.68 H2O. Calc'd: C, 64.25; H, 4.86; N, 11.29. Found: C, 64.24; H, 4.83; N, 11.40.
Figure imgf000085_0001
1 ,2,3,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-N-methyl-N,7- diphenyl-4H-1 ,4-benzodiazepine-4-carboxamide, dihydrochloride.
A. 7-Phenyl-1 ,2,3,5-tetrahydro-N-methyl-N-phenyl-4H-1 ,4- benzodiazepine-4-carboxamide
A solution of 94 mg (0.55 mmol) of N-methyl-N-phenylcarbamyl chloride in 1.5 mL of CH2CI2 was added over 3 min. to a stirred mixture of 115 mg (0.5 mmol) of Compound B of Example 12 in 3 mL of CH2CI2 and 2.5 mL of 1 N NaOH at 0°C. After 1.5 h the reaction was diluted with CH2CI2 and water and partitioned. The aqueous layer was extracted with CH2CI2 (2x) and the combined organic layers were dried (Na2SO4) and concentrated to give 177 mg (99%) of Compound A as a glassy residue.
B. 1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N-methyl- N,7-diphenyl-4H-1 ,4-benzodiazepine-4-carboxamide, dihydrochloride Example 35 was prepared from Compound A as described for Compound D of Example 1. Chromatography (silica, 7% methanol, 0.5%ammonium hydroxide, 93% methylene chloride) followed by conversion to the hydrochloride salt provided Example 35 as a powder, m.p. 97-102°C. MS: (M+H)+ 438+ Analysis calculated for C27H27N5O »1.2 HCl -0.75 H2O 0.25 C4H 1 oO. Calc'd: C, 65.51 ; H, 6.32; N, 13.64; Cl, 8.29. Found: C, 65.55; H, 5.98; N, 13.50; Cl, 8.42.
Example 36
Figure imgf000086_0001
2,3,4,5,-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenyl-carbonyl)-7-(1-piperidinylsulfonyl)-1 H-1 ,4- benzodiazepine, monohydrochloride.
A. 2,3,4,5,-Tetrahydro-7-(1 -piperidinylsulfonyl)-1 H-1 ,4- benzodiazepin-2,5-dione
A stirred solution of Compound A of Example 1 (400 mg, 2.3 mmol) in 10 mL of chlorosulfuric acid was heated at 100°C for 6 h. The solution was poured into ice-water. The aqueous suspension was extracted with ethyl acetate. The combined organic extracts were dried and filtered. The filtrate was mixed with piperidine (0.2 mL) at 0°C. The reaction was allowed to proceed for 30 min. The resultant solution was washed wfth 10% HCl, sat. NH4CI solution, dried and concentrated. The residue was triturated with ether to give Compound A as a white solid (250 mg, 34%). (M-H)" 322.
B. 2,3,4,5,-Tetrahydro-7-(1-piperidinylsulfonyl)-1 H-1 ,4- benzodiazepine
To a stirred suspension of LAH (200 mg, 5 mmol) in glyme was added the Compound A portionwise (185 mg, 0.57 mmol). After completion of the addition, the mixture was heated at 80°C under argon for 4h. The mixture was cooled to 0°C and ethyl acetate (20 mL) and NH4OH (0.3 mL) solution were added successively. The mixture was allowed to stir at room temperature for 18h. The resultant suspension was filtered. The filtrate was concentrated to give Compound B as an oil (90 mg, 53%). (M-H)- 295 C . 2,3,4,5,-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-(1 -piperidinylsulfonyl)-1 H-1 ,4- benzodiazepine, monohydrochloride
Example 36 was prepared from Compound B using the 2 step procedure of Compound C of Example 2 followed by Compound D of Example 1. MS: (M+H)+ 530+ Analysis calculated for C29H31 N5O3S «1.1 HCl »0.2 toluene »0.5 C4H10O.
Calc'd: C, 62.22; H, 6.27; N, 11.20; S, 5.13; Cl, 6.23. Found: C, 62.38; H, 6.45; N, 11.18; S, 5.23; Cl, 6.29
Example 37
Figure imgf000087_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-pyridin-2-yl-1 H-1 ,4-benzodiazepine, trihydrochloride
A. 2,3,4,5-Tetrahydro-1 -(1 -triphenylmethyl-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-7-bromo-1 H-1 ,4- benzodiazepine
Triphenylmethylchloride (6.83 mmol, 1.9 g) was added to a solution of Example 11 (6.83 mmol, 3.15 g) and triethylamine (34 mmol, 4.7 mL) in acetonitrile (100 mL) and the reaction was stirred for 2 hr. The resulting homogeneous yellow solution was concentrated under reduced pressure and purified by flash chromatography to give 3.9 g (81%) of Compound A as a white solid. MS (M+H)+ 703. B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-pyridin-2-yl-1 H-1 ,4-benzodiazepine, trihydrochloride.
A mixture of Compound A (0.28 mmol, 200 mg), 2-(fr-n-butylstannyl) pyridine (1.4 mmol, 520 mg) and Pd(PPh3)4 (40 mg, 0.034 mmol) in degassed THF (3 mL) was heated to 75°C for 18 hr. The reaction was cooled to room temperature, diluted with 30 mL of MeOH and treated with 2.0 mL of TFA. The mixture was stirred for 12 hr, concentrated, purified by preparative HPLC and converted to the HCl salt to give 46 mg (30% for two steps) of Example 37 as a yellow solid. MS: (M+H)+ 460+ Analysis calculated for C-29H25N5O »3.09 HCl.
Calc'd: C, 60.07; H, 4.95; N, 12.24. Found: C, 60.72; H, 5.09; N, 12.16
Example 38
Figure imgf000088_0001
7-(2-Furanyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 38 was prepared as a green solid in 11% yield from Compound A of Example 37 and 2-(tributylstannyl)furan as described for Compound B of Example 37. MS: (M+H)+ 449+ Example 39
Figure imgf000089_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-(2-thienyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 39 was prepared as a green solid in 10% yield from Compound A of Example 37 and 2-(tributylstannyl)thiophene as described for Compound B of Example 37. MS: (M+H)+ 465
Example 40
Figure imgf000089_0002
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
Trifluoroacetic anhydride (0.4 mmol, 60 mL) was added to a solution of 2,3,4,5-tetrahydro-4-(1 -naphthalenylcarbonyl)-7-bromo-1 H-1 ,4- benzodiazepine (prepared as described in Example 1 1 , 0.26 mmol, 100 mg) and NEt3 (1.04 mmol, 150 mL) in CH2CI2 (5 mL) and the homogeneous, colorless solution was maintained at room temperature for 1 hr. The reaction was concentrated, and the residue passed through a short silica gel column (gradient elution: 30% ethyl acetate/hexanes to neat ethyl acetate) to isolate a fluffy white solid which was taken to next step without further purification. This material was dissolved in toluene (2.0 mL) together with 4- (tributylstannyl)pyridine (0.52 mmol, 190 mg) and Pd(PPh3)4 (30 mg, 0.026 mmol) and the solution was purged with argon for 15 minutes. The homogeneous brown solution was heated to 115°C for 20 hrs to give a black heterogeneous solution. The reaction was concentrated and redissolved in MeOH/2N NaOH (aq) (5 mL:5mL) and stirred at room temperature for 30 minutes. MeOH was removed under reduced pressure and the reaction was partitioned between 10% isopropanol/CH2Cl2 and 2N NaOH/saturated NaCl (1 :1 , 10 mL) and extracted 2x with 10% isopropanol/CH2Cl2 (2X5mL). The pooled organic phase was dried over Na2Sθ4, concentrated and passed through a short silica gel column (eluted with 95:5:1 , CHCl3:MeOH:TEA) to remove polar impurities. The crude material was taken-up in 1 ,2-dichloroethane:AcOH (1 :1 , 2 mL total) and treated with 4- formyl imidazole (62 mg, 0.65 mmol) and NaBH(OAc)3 (0.78 mmol, 165 mg) and the solution was heated to 55°C for 2 hrs. The reaction was concentrated, partitioned between 10% isopropanol/CH2θ2 and 2N
NaOH/saturated NaCl (1 :1 , 10 mL) and extracted 2x with 10% isopropanol/CH2Cl2 (2X5mL). The pooled organic phase was concentrated, dissolved in MeOH/TFA (5 mL: 0.5 mL) and purified by prep HPLC (YMC S5 ODS 30 X 250 mm: Rt = 19-21 min; gradient elution with 0 to 100% buffer B over 30 min; Buffer A = MeOH:H2θ:TFA (10:90:0.1); Buffer B = MeOH:H2θ:TFA (90:10:0.1); 25 mL/min). The trifluoroacetate salt was converted to the HCl salt by lyophilizing in 1 M HCl (2X5mL) to give 75 mg (50% yield over 4 steps) of Example 40 as a bright yellow solid MS: (M+H)+ 460
Example 41
Figure imgf000091_0001
2,3,4,5-Tetrahydro-1-[3-(1 H-imidazol-2-yl)propyl]-4-(1- naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 3-[lmidazol-2-yl]-propenoic acid, ethyl ester. To a cooled (0°C) solution of sodium hydride (1.86g, 45.8 mmol,
60% dispersion in mineral oil, prewashed with THF and dried over N2) in
1 ,2-dimethoxyethane (DME, 20 mL) was added triethylphosphonoacetate (12g, 54.1 mmol) dissolved in DME (10 mL) dropwise over 15 minutes. The solution was stirred for 1 hr at ambient temperature followed by the addition of 2-imidazole acetaldehyde (4 g, 41.6 mmol) in 20 mL of DME. The solution was stirred and heated to reflux (85°C) for 15 minutes followed by cooling to 60°C for 1 hr. On cooling, the solution was concentrated to 1/2 volume and filtered. The solid was recrystallized from methanol/ethyl acetate/hexanes to give 5.1g (74%) of Compound A as a white crystalline solid. MS (M+H)+ 167+.
B. 3-[lmidazol-2-yl]-propanoic acid, ethyl ester
A solution of Compound A (4.01 g, 24.2 mmol) in absolute ethanol (100 mL, heated to dissolve) was hydrogenated using Pd/C (0.5g) at ambient temperature for 16 hr. Following removal of H2 under vacuum, the catalyst was removed by filtration through a bed of celite. The filtrate was concentrated under vacuum to give 4.0 g (100%) of Compound B as a white crystalline solid. MS (M+H)+ 169+. C . 3-[N-Triphenylmethyl-imidazol-2-yl]-propanoic acid, ethyl ester
Compound B was prepared from Compound A as described for Compound A of Example 6, using methylene chloride as solvent and triethylamine as base. After aqueous workup, recrystallization from ethyl acetate/hexanes afforded Compound B as a white microcrystalline solid. MS (M+H)+ 411+.
D . 3-[N-Triphenylmethyl-imidazol-2-yl]-propan-1-ol A solution of Compound C (0.80g, 1.95 mmol) in THF (15 mL) was cooled to 0°C under argon and a 1M solution of lithium aluminum hydride (2 mL, 2 mmol) was added dropwise with stirring. The reaction was stirred at ambient temperature for 16 hr. Water (2 mL) was added slowly and the solution was concentrated. Water (40 mL) and ethyl ether (60 mL) were added and the layers were separated. The ether layer was dried (MgSθ4) and concentrated. The residue was chromatographed (flash silica, 10:1 methylene chloride:methanol). Fractions containing product were pooled and concentrated to give 680 mg (95%) of Compound D as a white crystalline solid. MS (M+H)+.
E . 3-[N-Triphenylmethyl-imidazol-2-yl]-propanal
A solution of oxalyl chloride (0.3 mL, 0.6 mmol) in 2 mL methylene chloride was cooled to -63°C under argon. DMSO (0.056mL, 0.8 mmol) in methylene chloride (0.5 mL) was added over 10 min followed by addition of Compound D (147 mg, 0.4 mmol) in methylene chloride (6 mL) over 15 min keeping the reaction temperature below -50°C. The resulting clear solution was stirred for 50 min at -63°C. A solution of triethylamine (0.25 mL, 1.8 mmol) in methylene chloride (1 mL) was added over 15 min keeping the solution below -50°C. The mixture was stirred for 15 min followed by addition of 1 M potassium hydrogen sulfate (4.5 mL), water (20 mL) and ethyl ether (60 mL). The layers were separated and the aqueous layer was made basic using half saturated aqueous sodium bicarbonate and washed with ethyl acetate (3x30 mL). The combined organic layers were dried (MgSθ4) and concentrated to yield 146 mg (>99%) of Compound E as a yellowish gum. F. 2,3,4,5-Tetrahydro-4-(1 -naphthalenylcarbonyl)-7-phenyl- 1 H-1 ,4-benzodiazepine
A solution of Compound B of Example 12 (3.5 g, 15.63 mmol) and N.N-diisopropylethylamine (2.73 mL, 15.63 mmol) in DMF (10 mL) was added at once to a stirred solution of EDC ( 3.0 g, 15.63 mmol), HOBt (2.1 g, 15.63 mmol) and 1-naphthoic acid (2.42 g, 14.06 mmol) in DMF (20 mL). The mixture was stirred for 4 h, poured into water (200 mL) and the product was extracted with ethyl acetate (2X100 mL). The combined ethyl acetate layers were washed with water (3X200 mL), brine (100 mL), dried (MgS04), concentrated and chromatographed (silica gel, 50% ethyl acetate/hexane). Fractions containing the desired compound were collected and concentrated to yield Compound A as a clear oil (4.4 g, 93%), (M+H)+ 379+.
G. 2,3,4,5-Tetrahydro-1-[3-(1-triphenylmethyl-imidazol-2- yl)propyl]-4-(1-naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4- benzodiazepine
A solution of Compound E (109 mg, 0.29 mmol) and Compound F (100 mg, 0.26 mmol) were dissolved in 1 ,2-dichloroethane (10 mL). Acetic acid (0.1 mL) was added followed by sodium triacetoxyborohydride (84 mg, 0.40 mmol) . The mixture was stirred at 50°C for 2h. Saturated NaHCO3 (10 mL) was added and the mixture was concentrated, partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, dried (MgSθ4), concentrated and chromatographed (silica gel, 40% ethyl acetate/hexane). Fractions containing the desired compound were collected and concentrated to yield Compound G as a clear glass (100 mg, 47%), MS (M+H)+ 729+.
H . 2,3,4,5-Tetrahydro-1-[3-(1 H-imidazol-2-yl)propyl]-4-(1 - naphthalenylcarbonyl)-7-pheny 1-1 H-1 ,4-benzodiazepine, dihydrochloride.
A solution of Compound G (70 mg, 0.096 mmol) in methylene chloride (7 mL), TFA (7 mL), and triethylsilane (0.36 mg, 0.50 mL, 0.31 mmol) was stirred for 30 min at room temperature. The mixture was concentrated and the residue was dissolved in methylene chloride (60 mL) and concentrated. This procedure was repeated five times to yield the crude product as a white sticky solid in quantitative yield. This crude solid was purified by preparative HPLC (YMC S-5 ODS-A column, 30 X 250 mm; solvent A, 0.1% TFA in 90% water, 10 % methanol; solvent B, 0.1% TFA in 10% water, 90% methanol: 20-100% B in 60 min, flow rate 25 mlJmin). Fractions containing the desired product were combined, concentrated and lyophilized. This lyophilate was dissolved in methanol (0.5 mL) and 1 N HCl (5mL). This mixture was concentrated and lyophilized. This procedure was repeated to provide Example 41 as a white solid (15 mg, 28%). MS (M+H)+ 487+ 1 H-NMR (CD3OD, 400 MHz) d 8.05-7.00 (16H, m), 6.20 (1 H, m), 4.47-4.26
(2H, dd, J=15.0), 4.17 (1 H, m), 4.08 (1H, m), 3.48 (1H, m), 3.43 (1H, m), 3.33 (1 H, m), 3.12 (1 H, t), 3.06 (1 H, t), 2.98 (1 H, m), 2.16 (1 H, q), 2.04 (1 H, q).
Example 42
Figure imgf000094_0001
7-Bromo-2,3,4,5-tetrahydro-4-(1 H-imidazol-4-ylmethy l)-1 -(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 42 was prepared as an off white solid from 7-bromo-1 ,4- benzodiazepine (prepared as described in Compound B of Example 11 ) using the following procedure: Compound A of Example 4; Compound B of Example 4; Compound C of Example 4; Compound D of Example 1 , using methylene chloride as solvent, purification by prep HPLC (YMC S5 ODS 30 X 250 mm; gradient elution with 0 to 100% buffer B over 45 min; buffer A = MeOH:H2θ:TFA (10:90:0.1 ); buffer B = MeOH:H2θ:TFA (90:10:0.1); 25 mL/min) and conversion to the HCl salt by lyophilization from 1M HCl. MS (M+H+) 462.1 H-NMR (CD3OD): 3.5 (br s, 2H), 3.80 (m, 2H), 4.80 (br,
2H), 5.30 (br, 2H), 6.60 (m, 1 H), 7.15-8.15 (m, 11 H), 9.10 (s, 1 H).
Figure imgf000095_0001
8-Chloro-2,3,4,5-tetrahydro-4-(1 H-imidazol-4-ylmethyl)- 1 -(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 43 was prepared as an off white solid from Compound B of Example 2 as described for Example 42.
MS (M+H+) 459. 1 H-NMR (CD3OD): 3.40-3.80 (br s, 4H), 4.4(br., 2H), 4.7
(br., 2H), 5.20 (br., 2H), 6.65 (d, 1 H), 7.00-8.15 (m, 16 H), 9.00(s, 1 H).
Example 44
Figure imgf000095_0002
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-1 -(1- naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 44 was prepared as an off white solid from Compound B of Example 12 as described for Example 42. MS (M+H+) 459. 1 H-NMR (CD3OD): 3.40-3.80 (br s, 4H), 4.4(br, 2H), 4.7
(br, 2H), 5.20 (br, 2H), 6.65 (d, 1 H), 7.00-8.15 (m, 16 H), 9.00 (s, 1 H).
Figure imgf000096_0001
2,3,4,5-Tetrahydro-1 ,4-bis(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H- 1 ,4-benzodiazepine, dihydrochloride.
Example 45 was prepared as an off white solid from Compound B of Example 12 as described for Compound D of Example 1 , using methylene chloride as solvent, 4.3 equivalents of 4-formylimidazole, 4.3 equivalents of sodium triacetoxyborohydride and with stirring for 4 hours. MS (M+H+) 385. 1 H-NMR (CD3OD): 3.5 (br s, 4H), 4.60 (br, 2H), 4.9 (br,
4H), 7.2-8.0 (m, 10 H), 8,90 (s, 1H), 9.05 (s, 1 H).
Example 46
Figure imgf000096_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trifluoroacetate. Lithium aluminum hydride (1 M in THF, 15 mL, 15 mmol) was added to a suspension of Example 12 (0.25 g, 0.55 mmol) in THF (10 mL). The suspension was refluxed for 5 hr, cooled to 0°C, and 20% aqueous NaOH (10 mL) and H2O (10 mL) were added. The mixture was saturated with NaCl and extracted with CH2CI2 (2x 50 mL). Drying over Na2Sθ4 and evaporation of the solvent gave a solid (0.21 g) which was dissolved in MeOH/TFA (10:1) and purified by prep HPLC (YMC S5 ODS 30 X 250 mm; gradient elution with 0 to 100% buffer B over 45 min; Buffer A = MeOH:H2θ:TFA (10:90:0.1); Buffer B = MeOH:H2θ:TFA (90:10:0.1); 25 mL/min) to provide Example 46 (50 mg) as an off white solid. MS (M+H+) 445. Analysis calculated for C30H28 4O »2 HCl -0.3 H2O.
Calc'd: C, 68.90; H, 5.90; N, 10.71. Found: C, 68.94; H, 5.78; N, 10.43.
Example 47
Figure imgf000097_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-methoxy-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 47 was prepared as an off white solid from 6-hydroxy- isatoic anhydride by the following procedure: Compound A of Example 1 , with refluxing for 18 hr, and washing of the precipitate with water; formation of the methyl ether by stirring with 1.3 equivalents of methyl iodide in DMF in the presence of K2CO3 at room temperature for 12 hrs; Compound B of
Example 1 , with quenching with 20% NaOH and water followed by extraction with CH2CI2; Compound C of Example 2, with the product carried on without chromatography; Compound D of Example 1 , using methylene chloride, stirring for 5 hours and purification by flash chromatography (94.5:5:0.5, CH2Cl2:MeOH:NH4θH) before formation of the hydrochloride salt. Analysis calculated for C-24H24N4O2 »2 HCl »0.61 H2O. Calc'd: C, 60.50; H, 5.53; N, 11.29. Found: C, 60.51 ; H, 5.59; N, 11.14
Example 48
Figure imgf000098_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-7-carboxylic acid, dihydrochloride.
n-Buϋ (2.5 M in THF, 0.22 mL, 0.55 mmol) was added to a solution of Example 11 (0.12 g, 0.26 mmol) in THF (10 mL) at -78°C. The resulting brown solution was stirred for 4 min at -78°C, purged with CO2 for 20 min and quenched with acetic acid/water (2:1 , 2 mL). The solvent was evaporated, the residue was dissolved in methylene chloride, and the solution was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by prep HPLC (YMC S5 ODS 30 X 250 mm; gradient elution with 0 to 100% buffer B over 45 min; Buffer A = MeOH:H2θ:TFA (10:90:0.1); Buffer B = MeOH:H2θ:TFA (90:10:0.1); 25 mL/min) and the product was converted to the HCl salt by lyophilization from 1M HCl (5 mL) to provide Example 48 (50 mg, 45%) as an off white solid. MS (M+H+) 427. H-NMR (CD3OD): 3.05 (br m, 1 H), 3.20 (m, 1 H), 4.00 (br s, 1 H), 4.20 (br s,
1 H), 4.40 (br d, 1 H), 4.50 (br s, 1 H), 4.65 (s, 1 H), 5.05 (s, 1 H), 6.60 (d, 1 H), 7.19-8.20 (m, 11 H), 8.85 (s, 1H), 8.95(s, 1H). Example 49
Figure imgf000099_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-5-ylmethyl)-4-(1- naphthalenylcarbonyl)-7-cyclohexyl-1 H-1 ,4-benzodiazepine, 2.5 hydrochloride.
n-Buϋ (2.5M in THF, 1.4 mL, 3.5 mmol) was added to a solution of Example 11 (0.68 g, 1.4 mmol) in THF (15 mL) at -78°C. The resulting brown solution was stirred for 5 min. at -78°C and cyclohexanone (1.5 ml, 14.4 mmol) was added. After stirring at -78°C for 10 min., the reaction was quenched with sat. NH4CI (3 mL) and sat. NaHCθ3 (10 mL). The aqueous solution was extracted with CH2CI2. The organic phase was dried (Na2Sθ4) and evaporated. The residue was purified by chromatography (silica gel, 10% CH3OH, 0.5% AcOH in CH2CI2 ) to give the crude alcohol
(80 mg) as well as a 25% yield of Example 50. TFA (3 mL) was added to the crude alcohol (40 mg) in CH2CI2 (15 mL) at -78°C. The resulting blue solution was treated with solid NaBH4 (0.7 g, 18.5 mmol). The mixture was warmed to room temperature and quenched with NH4OH (10 mL). The solution was diluted with CH2CI2 (20 mL) and washed with aqueous NaOH (1N, 10 mL) and brine (10 mL). Drying over Na2Sθ4 and evaporation of solvent gave a solid which was converted to its HCl salt by lyophilization from 1M HCl to provide Example 49 as a yellow solid (30 mg). MS (M+H+) 465.
1 H-NMR (CD3OD): 1.50-2.40 (m, 10H), 2.89 (m, 1H), 3.20 (m, 2H), 4.00 (br s,
1 H), 4.20 (br s, 1 H), 4.40 (br d, 1 H), 4.50 (br s, 1 H), 4.65 (s, 1 H), 4.95 (s, 1 H), 6.15 (d, 1 H), 7.19-8.10 (m, 11 H), 8.85 (s, 1 H), 8.95 (s, 1 H).
Figure imgf000100_0001
7-Butyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
See Example 49 for the preparation of Example 50.
MS (M+H+) 439
1 H-NMR (CD3OD): 0.5-2.40 (m, 9H), 2.9 (m, 2H), 3.20 (m, 2H), 4.00 (br s,
1 H), 4.20 (br s, 1 H), 4.40 (br d, 1 H), 4.50 (br s, 1 H), 4.65 (s, 1 H), 4.95 (s, 1 H), 6.00 (br s, 1H), 7.19-8.10 (m, 11 H), 8.85 (s, 1H), 8.95(s, 1H).
Example 51
Figure imgf000100_0002
1 -[[2-(2-Aminoethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro- 4-(1 -naphthalenylcarbony l)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 51 was prepared by the following 2 step procedure. Tetrahydro-4-(1 -naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine (prepared as described in Example 12) was reductively alkylated with Compound B of Example 20 as described for Compound D of Example 1 , with stirring for 18 hours. Without workup, the mixture was subjected to flash chromatography (silica, 60 % ethyl acetate-hexanes) to afford the bis-Boc analog. Deprotection and purification as described in Compound C of Example 20 afforded Example 51 as an off-white powder. MS (M+H)+ 502 Analysis calculated for C32H31N5O «3 HCl -0.5 H2O.
Calc'd: C, 61.99; H, 5.69; N, 11.29. Found: C, 61.68; H, 6.07; N, 11.22.
Example 52
Figure imgf000101_0001
1-[[2-(Aminomethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro- 4-(1 -naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 52 was prepared from tetrahydro-4-(1- naphthalenylcarbonyl)-7-phenyl-1H-1 ,4-benzodiazepine and [2-(2-[[(1 ,1- dimethyl)-ethoxycarbonyl]amino]methyl)-1-[(1 ,1-dimethyl)-ethoxycarbonyl]- imidazol-4-yl]carboxaldehyde (see Example 21 ) as described for Example
51.
MS (M+H)+ 488 Analysis calculated for C31 H29N5O »3 HCl.
Calc'd: C, 62.37; H, 5.40; N, 11.73. Found: C, 62.13 H, 5.67; N, 11.73. Example 53
Figure imgf000102_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-8-[N,N-bis(phenyl-methyl)amino]-1 H-1 ,4- benzodiazepine, trihydrochloride.
Sodium triacetoxyborohydride (0.079 g, 0.37 mmol) was added to a solution of Example 26 (0.50 g, 0.12 mmol), benzaldehyde (0.04 g, 0.37 mmol) and AcOH (1 mL) in CH2CI2 (1 mL). After stirring for 16 hr, the reaction was diluted with CH2CI2 (10 mL), NH4OH (3 mL) and NaHCO3 (3 mL), and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over MgSθ4, filtered and concentrated. The residue was treated with HCI/ether, a yellow solid was formed which was triturated with ether several times and dried under vacuum to afford Example 53 (0.43 g, 60%).
MS (M+H)+ 579 1 H NMR ( 270 MHz, CD3OD): d 8.8 (d, 1H, J = 20 Hz), 8.04-7.9 (m, 2H), 7.6-
7.2 (m, 18 H), 7.0 (s, 0.5H), 5.87 (s, 0.5H), 4.95-4.8 (m, 5H), 4.5-4.1 (m, 3H), 3.85 (m, 1 H), 3.4-3.2 (m, 2H), 3.0 (m, 1H).
Example 54
Figure imgf000103_0001
N-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-yl-methyl)-4-(1 - naphthalenyl-carbonyl)-1 H-1 ,4-benzodiazepin-8- yljphenylsulfonamide, dihydrochloride.
Benzenesulphonamide (0.024 g, 0.13 mmol) was added to a solution of Example 26 (0.50 g, 0.12 mmol) and triethylamine (0.019 mL, 0.13mmol) in CH2CI2 (1 mL). After stirring for 16 hr, the reaction was diluted with CHCI3 (10 mL) and NaHCO3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgSθ4, filtered and concentrated. The residue was treated with HCI/ether, a yellow solid was formed which was triturated with ether several times and dried under vacuum to afford Example 54 (0.64.2 g, 83 %) as a light brown solid. MS (M+H)+ 538 1 H NMR (270 MHz, CD3OD): d 8.8 (d, 1 H, J = 20 Hz), 8.1 -7.23 (m, 13H), 7.1
(d,0.5H, J = 8 Hz), 7.0 (d, 0.5H, J = 8Hz ), 6.9 (d, 0.5H, J = 8Hz), 6.62 (d, 0.5H, J = 8Hz), 6.12 (d, 0.5H, J = 8Hz), 5.71 (d, 0.5H, J = 8Hz) 4.55 (m, 1H), 4.55-3.9 (m, 3H), 3.45-3.25 (m, 2H), 3.0-2.8 (m, 2H).
-lot Example 55
Figure imgf000104_0001
N-Phenyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-7-carboxamide, dihydrochloride.
A mixture of Example 48 (50 mg, 0.11 mmol), PyBROP (0.28 g, 0.6 mmol), DMAP (0.04 g, 0.3 mmol) and DIEA (0.3 g, 2.3 mmol) in DMF (5 mL) was stirred for 5 min, aniline (1 mL, 11 mmol) was added and the resulting homogeneous solution was stirred for two days. After removing DMF, the residue was purified by prep HPLC (YMC S5 ODS 30 X 250 mm: Rt = 22-23 min; gradient elution with 0 to 100% buffer B over 45 min; Buffer A = MeOH:H2θ:TFA (10:90:0.1); Buffer B = MeOH:H2θ:TFA (90:10:0.1); 25 mL/min) and conversion to the HCl salt was accomplished by lyophilizing from 1 M HCl (5 mL) to provide Example 55 (40 mg, 34%) as a yellow solid.
MS (M+H)+ 502
1 H-NMR (CD3OD): 3.10 (br m, 1 H), 3.25 (m, 1 H), 4.10 (br s, 1H), 4.25 (br s, 1 H), 4.45 (br d, 1 H), 4.55 (br s, 1 H), 4.60 (s, 1 H), 5.10 (s, 1 H), 6.64 (d, 1 H), 7.19-8.20 (m, 16H), 8.85 (s, 1H), 8.95(s, 1 H).
Example 56
Figure imgf000105_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-3- methylbenzamide, dihydrochloride.
Example 56 was prepared from m-toluoyl chloride and Example 26 as described for Example 27, with stirring for 16 hr. The HCl salt was formed directly from the crude product to provide a 94% yield of Example 56 as a brown solid. MS (M+H)+ 516 H NMR (270 MHz, CD3OD): d 8.8 (d, 1 H, J = 20 Hz), 8.15-7.2 (m, 14H), 6.8 (d, 0.5 H, J = 7 Hz), 5.95 (d, 0.5 H, J = 7 Hz), 4.98 (s, 1 H), 4.7-4.19 (m, 3H), 4.19-3.9 (m, 1H), 3.52-3.2 (m, 1.5H), 3.25-3.15 (m, 0.5H), 3.1-2.8 (m, 1 H), 2.46-2.33 (m, 3H).
Example 57
Figure imgf000106_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-4- methylbenzamide, dihydrochloride.
Example 57 was prepared from p-toluoyl chloride and Example 26 as described for Example 56. MS (M+H)+ 516 1 H NMR (270 MHz, CD3OD): d 8.8 (d, 1 H, J = 20 Hz), 8.15-7.72 (m, 5H), 7.7-
7.2 (m, 9H), 6.77 (d, 0.5H, J = 7 Hz), 5.92 (d, 0.5H, J = 7 Hz), 4.98 (s, 1 H), 4.7-4.19 (m, 3H), 4.12-3.9 (m, 1 H), 3.52-3.2 (m, 1.5H), 3.25-3.15 (m, 0.5H), 3.1-2.8 (m, 1 H), 2.46-2.33 (m, 3H).
Example 58
Figure imgf000107_0001
3-Chloro-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-4-(1 naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]benzamide, dihydrochloride.
Example 58 was prepared from 3-chlorobenzoyl chloride and Example 26 as described for Example 56. MS (M+H)+ 536 1 H NMR (270 MHz, CD3OD): d 8.87 (d, 1 H, J = 20 Hz), 8.05-7.82 (m, 4H),
7.75-7.2 (m, 10H), 6.8 (d, 0.5 H, J = 8 Hz), 5.9 (d, 0.5 H, J = 8 Hz), 4.96 (s, 1 H), 4.65-3.9 (m, 4H), 3.4-3.3 (m, 2H), 3.05-2.9 (m, 1H).
Example 59
Figure imgf000107_0002
7-Bromo-2,3,4,5,-tetrahydro-1-[[2-[(dimethylamino)-methyl]-1 H- imidazol-4-yl]methyl]-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A stirred suspension of Example 11 (100 mg, 0.22 mmol), paraformaldehyde (10 mg, 0.33 mmol) and dimethylamine (40% in water, 0.041 mL) in acetic acid was heated at 90°C for 18 h. The mixture was partitioned between ethyl acetate and sat. NaHCθ3 solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by flash chromatography (30% MeOH, 69% ethyl acetate and 1 % NH4OH) to give a solid which was dissolved in methanol. 1 N HCl in ether was added, and the solvent removed to give Example 59 as a yellow solid (30 mg, 23%). MS (M+H)+ 518
Example 60
Figure imgf000108_0001
7-(4-Chlorophenyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A solution of Compound A of Example 37 (0.142 g, 0.2 mmol) in DMF (5 mL) and THF (10 mL) was degassed for 5 min with argon. Tetrakis(triphenylphosphine)palladium (0.10 g, 0.08 mmol) was added and the solution was degassed for 20 min with argon. Sodium carbonate (0.11 g, 0.8 mmol) in degassed H2O (2 mL) was added, followed by 4- chlorobenzeneboronic acid (0.17 g, 1.1 mmol). The resulting solution was heated to 110°C for 14 hrs. The solvent was evaporated, the residue was dissolved in CH2CI2 (15 mL), and the solution was treated with HSiMe3 (3 eq) and TFA (10 eq). The solvent was evaporated and the residue was purified by prep HPLC and converted to HCl salt as described for Example 48 to provide Example 60 (40 mg, 40%) as a gray solid. MS (M+H)+ 493 1 H-NMR (CD3OD, 300MHz) d 2.95 (br m, 1 H), 3.30 (m, 1 H), 4.00 (br s, 1 H),
4.20 (br s, 1 H), 4.40 (br d, 1 H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), 6.05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).
Example 61
Figure imgf000109_0001
7-(3-Aminophenyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-4-(1-naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
Compound 61 was prepared as a gray solid in 45% yield from Compound A of Example 37 and 3-aminobenzeneboronic acid (0.17 g, 1.1 mmol) as described for Example 60. MS (M+H)+ 474
1 H-NMR (CD3OD, 300MHz) d 2.95 (br m, 1H), 3.30 (m, 1H), 4.00 (br s, 1H),
4.20 (br s, 1 H), 4.40 (br d, 1 H), 4.60 (m, 1 H), 4.65 (m, 1 H), 5.05 (s, 1 H), 6.05 (d, 1H), 7.00 (d, 1 H), 7.15-8.10 (m, 13H), 8.85 (s, 1 H), 8.95(s, 1 H).
Example 62
Figure imgf000110_0001
1 -Methyl-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-1 H-pyrrole-2- carboxamide, trihydrochloride.
Example 26 (0.050 g, 0.12 mmol) was added to a solution of EDC (0.071 , 0.37 mmol), HOAt (0.051 g, 0.37 mmol) and 1-methyl-2- pyrrolecarboxylic acid (0.046 g, 0.37 mmol) in DMF (1 mL). After stirring for 16 hr, the mixture was diluted with CHCI3 (10 mL) and NaHCO3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgSθ4, filtered and concentrated. The residue was purified on a silica gel column eluting with CHCI3 followed by CHCl3/MeOH (19/1). The product was treated with HCI/ether to afford a yellow solid which was triturated with ether few times and dried under vacuum to afford Example 62 (0.007 g, 11 %) as a light brown solid. MS (M+H)+ 505 H NMR ( 270 MHz, CD3OD): d 8.88 (d, 1 H, J = 21 Hz), 8.07-7.9 (m, 2.5H),
7.72-7.4 (m, 5H), 7.3 (d, 0.5H, J = 8Hz), 7.23 (d, 0.5H, J = 8Hz), 7.16 (d, 0.5H, J = 8 Hz), 7.0 (m, 0.5H), 6.95-6.85 (m, 1 H), 6.7 (d, 0.5H, J = 8Hz), 6.15-6.1 (m, 1 H), 5.92 (d, 0.5H, J = 8Hz), 5-4.9 (m, 2H), 4.65-4.15 (m, 4H), 3.98-3.9 (d, 3H, J = 10), 3.43-3.3 (m, 2.5H), 3.05-2.87 (m, 1 H). Example 63
Figure imgf000111_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-3- furancarboxamide, dihydrochloride.
Example 63 was prepared as a yellow solid from Example 26 and 3-furoic acid as described for Example 62. MS (M+H)+ 492 1 H NMR (270 MHz, CD3OD): d 8.88 (d, 1 H, J = 20 Hz), 8.25 (d, 1H, J = 16
Hz), 8.13-7.38 (m, 9H) 7.38 (d, 0.5H, J = 6 Hz), 7.25 (0.5 H, J = 6Hz) 7.19 (d, 0.5H, J = 8Hz), 6.95 (d, 0.5H, J = 17 Hz), 6.72-6.68 (m, 1 H), 5.93 (d, 0.5H, J = 8Hz), 5.0-4.9 (m, 2H), 4.66-3.91 (m, 3.5H), 3.4-3.3 (m, 2H), 3.05-2.89 (m, 1 H).
Example 64
Figure imgf000112_0001
7-(3-Chlorophenyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Compound 64 was prepared as a gray solid in 55% yield from Compound A of Example 37 and 3-chlorobenzeneboronic acid (0.17 g, 1.1 mmol) as described for Example 60. MS (M+H)+ 493 1 H-NMR (CD3OD, 300MHz) d 2.95 (br m, 1H), 3.30 (m, 1H), 4.00 (br s, 1H),
4.20 (br s, 1 H), 4.40 (br d, 1 H), 4.60 (m, 1 H), 4.65 (m, 1 H), 5.05 (s, 1 H), 6.05 (d, 1 H), 7.00 (d, 1 H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).
Example 65
Figure imgf000112_0002
2-Methyl-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]benzamide, dihydrochloride. Example 65 was prepared as a light yellow solid in 23% yield from o-toluoyl chloride and Example 26 as described for Example 56. MS (M+H)+ 516 1 H NMR ( 270 MHz, CD3OD): d 8.8 (d, 1 H, J = 20 Hz), 8.05-7.2 (m, 13.5H),
7.1 (d, 0.5H, J = 6Hz), 6.7 (d, 0.5H, J = 8 Hz), 5.95 (d, 0.5H, J = 8 Hz), 5.1 -4.9 (m, 2H), 4.7-3.9 (m, 3H), 3.45-3.3 (m, 2H), 3.8-2.9 (m, 1H), 2.5-2.4 (d, 3H, J = 15Hz).
Example 66
Figure imgf000113_0001
N-Phenyl-N'-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]urea, dihydrochloride.
Phenyl isocyanate (0.016 mL, 0.15 mmol) was added to a solution of Example 26 (0.050 g, 0.12 mmol) and triethyl amine (0.020 mL, 0.15 mmol) in CH2CI2 (1 mL). After stirring for 16 hr, the reaction was diluted with CHCI3 (10 mL) and NaHCθ3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were dried over MgSθ4, filtered and concentrated. The residue purified on a silica gel eluting with (19/1) CHCI3/CH3OH. The appropriate fractions were concentrated and the residue was treated with HCI/ether. The solid was triturated with ether several times and dried under vacuum to afford Example 66 (0.018 g, 25 %) as a light yellow solid.
MS (M+H)+ 517
-lit 1 H NMR ( 400 MHz, CD3OD): d 8.83 (d, 1 H, J = 19Hz), 8.07-7.89 (m, 2H), 7.68-7.2 (m, 11.5H), 7.07-6.98 (m, 1H) 6.85 (d, 0.5H, J = 6Hz), 6.4 (d, 0.5H, J = 8Hz), 5.89 (d, 0.5H, J = 8Hz), 5.1-4.9 (m, 1H), 4.69-3.9 (m, 4H), 3.45-3.3 (m, 2H), 3.05-2.88 (m,1 H).
Example 67
Figure imgf000114_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-(3-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 67 was prepared as a yellow solid in 8% yield from Compound A of Example 37 and 3-(tributylstannyl)pyridine as described for Compound B of Example 37. MS: (M+H)+ 460
Example 68
Figure imgf000114_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-9-methoxy-4-(1 naphthalenylcarbonyl)-1 H-1 ,4-diazepine, dihydrochloride. Example 68 was prepared as a light yellow solid from 8- methoxyisatoic anhydride and glycine ethyl ester hydrochloride as described in the following multistep sequence: Compound A of Example 1 ; Reduction was accomplished by refluxing a solution of the dione with 5 eq of borane- THF in THF for 20 hr; cooling to 0°C, acidifying with 3N HCl, heating at 100°C for 30 min, neutralizing with 5N NaOH followed by extraction with methylene chloride; Compound C of Example 2; Compound D of Example 1. MS (M+H)+ 413 IR: (KBr):- 2926, 2837, 1732, 1630, 1580, 1474, 1252, 1078, 804, 781 cm'l .
Example 69
Figure imgf000115_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-pyrido[2,3-e]-1 ,4-diazepine, trihydrochloride.
A. 2,3,4,5-Tetrahydro-7-bromo-1 H-pyrido[2,3-e]-1 ,4- diazepin-5-one
To a solution of Compound A of Example 23 (100 mg, 0.61 mmol) in acetic acid (10 mL) was added bromine (32 μL, 0.61 mmol). The mixture stirred for 30 minutes after which another equivalent of bromine (32 μL) was added to drive the reaction to completion. After an additional 30 minutes, the reaction was diluted with 30 mL H2O and neutralized to pH 7 with 5 N NaOH. The mixture was extracted with E.2O (50 mL) then with CH2CI2 (2 x 100 mL). The organic layers were combined, washed with brine and dried over Na2SO4.
Concentration gave Compound A as a solid (116 mg, 79%). MS (M+CH3CN)+ 283. B. 2,3,4,5-Tetrahydro-7-phenyl-1 H-pyrido[2,3-e]-1 ,4- diazepin-5-one
A solution of Compound A (27 mg, 0.11 mmol), PhB(OH)2 (34 mg, 0.28 mmol), and K3PO4 (59 mg, 0.28 mmol) in anhydrous DMF (0.6 mL) and anhydrous THF (0.6 mL) was degassed by bubbling with a stream of N2 for 1 hour. To this solution was added recrystallized Pd(PPh3)4 and the solution was warmed to 65°C for 30 hours. The mixture was cooled to room temperature and diluted with CH2CI2 (6 mL). This was extracted with 10% LiCI and the aqueous layer back-extracted once with CH2CI2 (6 mL). The organic layers were combined and washed with 1 N HCl. The organic layer was discarded, and the aqueous layer was basified with 5 N NaOH and extracted with CH2CI2 (3 x 10 mL). These organic layers were washed once more with 10% LiCI, dried over Na2Sθ4 and concentrated to give Compound B as a white solid (18 mg, 70%). MS (M+H+CH3CN)+ 281.
C . 2,3,4,5-Tetrahydro-7-phenyl-1 H-pyrido[2,3-e]-1 ,4- diazepine
Compound C was prepared as described for Compound B of Example 23, with refluxing for 60 hours. The crude material was chromatographed (flash silica, 230-400 mesh, 5-10% MeOH/CHCl3) to give Compound C as a white solid (34%). MS (M+H+CH3CN)+ 267.
D . 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-pyrido[2,3-e]-1 ,4-diazepine, trihydrochloride.
Example 69 was prepared as a fluffy white solid in 36% overall yield from Compound C as described for Compound C of Example 23 and Compound D of Example 23, with a total of 6 aliquots of aldehyde and hydride necessary to drive the reaction to completion. MS (M+H)+ 460 Analysis calculated for C-29H25N5O »3 HCl.
Calc'd: C, 61.22; H, 4.96; N, 12.31. Found: C, 61.50 H, 5.21 ; N, 12.29. Example 70
Figure imgf000117_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[2- (methylthio)ethyl]-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Example 70 was prepared as a yellow solid from isatoic anhydride and L-methionine-O methyl ester hydrochloride as described in the following sequence: Compound A of Example 1 , with refluxing for 18 hours, evaporation of solvent and partitioning between 1 N hydrochloric acid and dichloromethane; Example 17, except that the free base was carried on; Compound C of Example 2, with flash chromatography on silica eluting with ethyl acetate.hexane (1:2); Compound D of Example 1. mp 145-150°C. MS (M+H)+ 456 Analysis calculated for C27H28N4OS *1.6 H2O »1.3 HCl.
Calc'd: C, 60.86; H, 6.15; N, 10.51; S, 8.65; Cl, 6.02. Found: C, 60.96; H, 5.67; N, 10.14; S, 8.39; Cl, 5.68.
Figure imgf000118_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 71 was prepared as a yellow solid from isatoic anhydride and D,L-phenylalanine-0 methyl ester hydrochloride as described for Example 70. mp 78-80°C. MS (M+H)+ 473 Analysis calculated for C31 H28N4O »1.6 H2O «1.8 HCl.
Calc'd: C, 65.66; H, 5.87; N, 9.88; Cl, 11.25. Found: C, 65.85; H, 5.68; N, 9.64; Cl, 11.55.
Example 72
Figure imgf000118_0002
2,3,4,5-Tetrahydro-3-(2-hydroxyethyl)-1 -(1 H-imidazol-4- ylmethyl)-4-(1-naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 72 was prepared as a white solid from isatoic anhydride and D,L-aspartate-0-dimethyl ester hydrochloride as described for Example 70, except that 5 equivalents of lithium aluminum hydride were used in the reduction step, and the final product was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 155-160°C. MS (M+H)+ 427 Analysis calculated for C26H26N4O2 *1.0 H2O «1.3 TFA. Calc'd: C, 57.95; H, 4.98; N, 9.45; Cl, 11.25. Found: C, 58.09; H, 4.71 ; N, 9.32; Cl, 11.55.
Example 73
Figure imgf000119_0001
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-3-[2- (methylthio)ethyl]-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate.
Example 73 was prepared from 2,3,4,5-tetrahydro-3-[2- (methylthio)ethylj-1 H-1 ,4-benzodiazepine (prepared from D, L-methionine-O methyl ester hydrochloride as described in Example 70) by the following procedure: Compound A of Example 4; Compound C of Example 2, carried on without purification; Compound C of Example 4; Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 130-135°C. MS (M+H)+ 456 Analysis calculated for C27H28N4OS »1.5 H2O »1.3 TFA.
Calc'd: C, 56.27; H, 5.15; N, 8.87; S, 5.07; F, 11.73. Found: C, 56.24; H, 4.84; N, 8.74; S, 5.10; F, 12.05.
Figure imgf000120_0001
(S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 74 was prepared as a white solid from isatoic anhydride and L-phenylalanine-0 methyl ester hydrochloride as described for Example 70, with final purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 152-154°C. MS (M+H)+ 473 Analysis calculated for C31 H28N4O -1.0 H2O «1.2 TFA. Calc'd: C, 63.94; H, 5.01 N, 8.93; Cl, 10.90. Found: C, 64.12; H, 4.87; N, 8.73; Cl, 11.01.
Example 75
Figure imgf000120_0002
4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. A. 7-Bromo-2,3,4,5-Tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-2,5-dione
A mixture of bromoisatoic anhydride (2.93 g, 12.1 mmol), D,L- phenylalanine-0 methyl ester hydrochloride salt (2.62 g, 12.1 mmol), dimethylaminopyridine (100 mg, catalytic) and pyridine (50 ml) was refluxed (bath temperature -140 °C) under argon for 48 hours. The solution was concentrated in vacuo to a semi-solid and the residue was suspended in 1 NHCI (200 mL) and dichloromethane (200 mL). The resultant precipitate was filtered and washed with dichloromethane (50 mL) and dried in vacuo at 50°C for 18 hrs to provide Compound A (1.1 g, 26 %) as a gray solid.
B. 7-Bromo-2,3,4,5-Tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a solution of Compound A (500 mg, 1.45 mmol) in ethylene glycol dimethyl ether (anhydrous, 50 mL) under argon at 0° C was slowly added a solution of BH3:THF (20 mL, 1 M solution in THF). The solution was allowed to warm to room temperature, heated to reflux for 18 hours, cooled to °C, quenched with methanol (5 mL), and concentrated in vacuo to an oil. The oil was treated with 6 M HCl ( 100 mL), on a steam bath for 2 hours, during which time partial dissolution occurred. The mixture was cooled to 0°C and adjusted to pH 10 with solid NaOH. The resultant mixture was partitioned in ethyl acetate (200 mL) and extracted with ethyl acetate (2 x 100 mL), dried (Na2S04) and concentrated in vacuo to provide Compound
B as a brown solid (300 mg, 0.94 mm, 65 %)
C . 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine
A mixture of Compound B (200 mg, 0.63 mmol), dichloromethane (5 mL), and aqueous sodium hydroxide (1 ml, 1 N) was combined and cooled to 0°C. Acetyl chloride (66 mL, 0.94 mmol) was added to the mixture, and after stirring for 2 hour at 0°C aqueous sodium hydroxide (20 ml, 1N) and dichloromethane (50 mL) were added, followed by extraction with dichloromethane (50 mL). The organic portions were combined, dried (Na2S04), and concentrated to a crude oil (230 mg, 100 %). D . 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
Example 75 was prepared as a white solid from Compound C as described for Compound D of Example 1 , with purification of the final product by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 112°C.
MS (M+H)+ 440 Analysis calculated for C22H23N4θBr »0.5 H2O «1.3 TFA.
Calc'd: C, 49.53; H, 4.27 N, 9.39; F, 12.42. Found: C, 49.44; H, 4.07; N, 9.34; F, 12.32.
Example 76
Figure imgf000122_0001
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-1 -(1 - naphthalenyl-carbonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, 1.5 hydrochloride.
Example 76 was prepared as a white solid from 2,3,4,5-tetrahydro-
3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (prepared as described in Example 71) by the following procedure: Compound A of Example 4; Compound C of Example 2, with catalytic pyridine and purification on silica eluting with hexane: ethyl acetate (4:1); Compound C of Example 4; Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 117-120°C. MS (M+H)+ 473 Analysis calculated for C3i H28N4θBr -0.8 H2O »1.52 TFA.
Calc'd: C, 61.92; H, 4.75 N, 8.48; F, 13.12. Found: C, 62.31 ; H, 4.40; N, 8.09; F, 12.76. Example 77
Figure imgf000123_0001
7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxamide, trifluoroacetate.
A. 7-Bromo-1 ,2,3,5-tetrahydro-3-(phenylmethyl)-4H-1 ,4- benzodiazepine-4-carboxamide
A mixture of Compound B of Example 75 (200 mg, 0.63 mmol, ), THF (20 mL), and trimethylsilylisocyanate (0.13 mL, 0.95 mmol) was stirred under argon at room temperature for 18 hours. Water was added to the solution (5 mL), followed by aqueous hydrochloric acid ( 20 ml, 1 N). The mixture was extracted with ethyl acetate (2 x 100 mL), the organic extracts were combined, dried (MgSO4), and concentrated in vacuo to provide
Compound A as a yellow solid (200 mg, 88 %)
B. 7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxamide, trifluoroacetate.
Example 77 was prepared as a white solid from Compound A as described for Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 162-165°C. MS (M+H)+ 440
Analysis calculated for C-21 H22 δOBr »0.3 H2O »1.2 TFA.
Calc'd: C, 48.24; H, 4.12 N, 12.02; Br, 13.72; F, 11.74. Found: C, 48.23; H, 3.91 ; N, 11.95; Br, 13.63; F, 11.39. Example 78
Figure imgf000124_0001
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride
A. 7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3- (phenylmethy l)-1 H-1 ,4-benzodiazepine
A mixture of Compound B of Example 75 (1.0 g, 3.15 mmol, ), THF (20 mL), DIEA (0.6 mL, 6.3 mmol) and methanesulfonyl chloride (0.5 mL, 6.3 mmol) was stirred under argon at room temperature for 2 hours. The mixture was partitioned in aqueous hydrochloric acid (100 ml, 1 N), and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were combined, dried (MgSO4) and concentrated under vacuum to provide an oil. The oil was flash chromatographed (50 g silica eluted with hexane:ethyl acetate (3:1) to provide Compound A as a clear oil (330 mg, 27 %).
B. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 4-(methyfsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride
To a stirred solution of Compound A (330 mg, 0.84 mmol), formyl imidazole (120 mg, 1.26 mmol), dichloroethane (10 mL) and acetic acid (2 mL) at room temperature was added sodium triacetoxyborohydride (267 mg, 1.26 mmole). The solution was stirred for 1 hour, diluted with ethyl acetate (20 mL) and ammonium hydroxide (2 ml, cone), and stirred for an additional 18 hours. The mixture was extracted with ethyl acetate (2 x 25 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (25 ml, saturated solution) and ammonium chloride (25 mL, sat aqueous solution), dried (Na2SO4), and concentrated in vacuo to a semi-solid. The crude was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and lyophilized to provide the TFA salt of Example 78 as a white solid (330 mg, 83 %), mp 118-120 °C. This material was dissolved in methanol (3 mL) and 1 M HCl (3 mL) was added. The solution was evaporated and the residue triturated with methylene chloride to provide Example 78 as a white solid, mp 178-180 °C. MS (M+H)+ 476 Analysis calculated for C21 H23N4θ2SBr «0.25 H2O »1.2 HCl.
Calc'd: C, 48.17; H, 4.75 N, 10.70; S, 6.12; Cl, 8.12; Br, 15.26. Found: C, 48.53; H, 4.60; N, 10.25; S, 6.95; Cl, 8.27; Br, 14.93.
Figure imgf000125_0001
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl- 3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
A. 4-Acetyl-2,3,4,5-tetrahydro-7-phenyl-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepine
To a solution of Compound C of Example 75 (500 mg, 1.39 mmol) in toluene (20 mL,), and NaHC03 (5 mL, sat solution) under argon was added a solution of phenylboronic acid (340 mg, 2.8 mmol, in 2 mL ethanol). Tetrakistriphenylphosphine palladium(O) (42 mg, 0.07 mmol) was added to the mixture and it was brought to reflux under argon for three hours. The mixture was poured into brine, extracted with ethyl acetate (2 x 100 mL), the organics combined and dried (MgS04), and concentrated in vacuo to provide a crude red oil, which was purified by flash chromatography (50 g silica eluted with hexane:ethyl acetate 1 :1 to provide Compound A as a white solid (290 mg, 59 %).
B. 4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 79 was prepared as a white solid in 79% yield from Compound A as described for Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). mp 120-123°C. MS (M+H)+ 437 Analysis calculated for C28H28N4O «1.3 H2O »1.05 TFA. Calc'd: C, 62.36; H, 5.50 N, 9.66; F, 10.32. Found: C, 62.42; H, 5.17; N, 9.61 ; F, 10.24.
Example 80
Figure imgf000126_0001
4-Acetyl-7-bromo-3-[(4-chloroρhenyl)methyl]-2,3,4,5-tetrahydro-
1 -(1 H-imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. D,L-N-(2-Amino-5-bromobenzoyl)-4-chlorophenylalanine
D,L-4-chlorophenylalanine (prepared from N-Boc-D,L-4- chlorophenylalanine and 4N HCl in dioxane with dimethyl sulfide) and 6- bromoisoatoic anhydride (1.0 g, 4.15 mmol) were combined in pyridine (50 mL) and the mixture was refluxed for 4 h. The mixture was cooled, concentrated and the residue was partitioned between water (200 mL) and ethyl acetate (200mL). The organic layer was washed with water (3X100mL), brine (50 mL), dried (MgSθ4) and concentrated to yield
Compound A as a yellowish glass (450 mg, 27 %), MS (M+H)+ 398.
B. 7-bromo-3-[(4-chlorophenyl)methyl]-2,3,4,5-tetrahydro- 1 H-1 ,4-benzodiazepin-2,5-dione
Compound A (450 mg, 1.13 mmol), EDC (737 mg, 3.85 mmol), and HOBt (519 mg, 3.85 mmol) were dissolved in DMF (10 mL) and DIEA (0.52 mL, 2.96 mmol) was added at once. The mixture was stirred for 16 h , poured into water (100 mL) and the product was extracted with ethyl acetate (2X50 mL). The combined ethyl acetate layers were washed with water (3X100 mL), brine (100 mL), dried (MgSO4) and concentrated to yield compound B as a brown glass (200 mg, 46 %), MS (M+H)+ 380.
C . 7-bromo-3-[(4-chlorophenyl)methyl]-2,3,4,5-tetrahydro- 1 H-1 ,4-benzodiazepine
Compound B (200 mg, 0.53 mmol) was dissolved in THF (10 mL) and borane (1 M in THF, 4 mL, 4 mmol) was added. The solution was refluxed for 3 h and cooled to room temperature. Methanol (5 mL) was added and the solution was concentrated. 5N HCl (10 mL) was added to the concentrate and the mixture was refluxed for 4 h. The mixture was cooled to room temperature, neutralized to pH 6 with 50% NaOH and extracted with methylene chloride (3X50 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and concentrated to yield compound C as a slightly yellow glass (60 mg, 32 %), MS (M+H)+ 352.
D . 4-Acetyl-7-bromo-3-[(4-chlorophenyl)methyl]-2, 3,4,5- tetrahydro-1 H-1 ,4-benzodiazepine Compound D (60 mg, 0.17 mmol) was dissolved in THF (5 mL) and
DIEA (30 μL, 0.17 mmol) was added followed by acetyl chloride (12 μL, 0.17 mmol). The solution was stirred for 30 min, concentrated, redissolved in ethyl acetate (50 mL) and washed with water (3X20 mL). The organic layer was dried (MgSθ4) and concentrated to yield Compound D as a light brown glass. E . 4-Acetyl-7-bromo-3-[(4-chlorophenyl)methyl]-2,3,4,5- tetrahydro-1-(1 H-imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride
Example E was prepared from Compound D as a white solid in 13% yield as described for Compound D of Example 1 , with purification by preparative HPLC (YMC S-5 ODS-A column, 30 X 250 mm; solvent A, 0.1% TFA in 90% water, 10 % methanol; solvent B, 0.1% TFA in 10% water, 90% methanol: 20-100% B in 60 min, flow rate 25 mL/min) and conversion to the HCl salt by adding 1 N HCl to methanol solution of the TFA salt and lyophilizing.
MS (M+H)+ 475
1 H-NMR (CD3OD, 400 MHz) d 8.85 (1 H, s), 7.49-7.15 (7H, m), 6.81 (1H, m),
4.60 (2H, ), 4.49-4.35 (2H, m), 3.63 (1 H, m), 2.84-2.63 (2H, m), 2.07 (2H, m), 1.94 (3H, s).
Example 81
Figure imgf000128_0001
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-y lmethyl)-3- (phenylmethyl)-l H-naphtho[2,3-e]-1 ,4-diazepine, monohydrochloride.
A. 2,3,4,5-Tetrahydro-3-(phenylmethyl)-1 H-naphtho[2,3-e]- 1 ,4-diazepin-2,5-dione
A solution of the 2,3-naphthyl analog of isatoic anhydride (prepared from 3-amino-2-naphthoic acid , 2.3 eq of triphosgene and triethyl amine in acetonitrile), D, L-phenylalanine (0.77g, 4.7 mmol) and pyridine hydrochloride (540 mg, 4.7 mmol) in pyridine (60 mL) was refluxed for 20 h under nitrogen followed by concentration to an oil. Water (100 mL) was added and the solution was triturated to give a brown solid. This material was filtered and dried under high vacuum to give 1.3g (87%) of Compound A as a brown solid. MS (M+H)+ 317.
B. 4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-l H-naphtho[2,3-e]-1 ,4-diazepine, monohydrochloride.
Example 81 was prepared as an offwhite solid from Compound A by the following procedure: Compound C of Example 80; Compound D of Example 80, with stirring for 1 hour and with purification by flash chromatography on silica with ethyl acetate.hexanes (1 :5-1 :1); Compound E of Example 80.
MS (M+H)+ 411
Analysis calculated for C26H26N4O «1.19 H2O «1.5 HCl. Calc'd: C, 64.44; H, 6.17 N, 11.02; Cl, 10.71. Found: C, 64.04; H, 6.38; N, 11.40; Cl, 10.90.
Example 82
Figure imgf000129_0001
N-Cyclohexyl-N'-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]urea, dihydrochloride.
Example 82 was prepared from cyclohexylisocyanate as described for Example 66, with column chromatography performed with CHCI3/CH3OH
(19/1 then 9/1). MS (M+H)+ 523 1 H NMR (270 MHz, CD3OD): d 8.83 (d, 1 H, J = 19 Hz), 8.0-7.89 (m, 2.5H) 7.63-7.3 (m, 6.5H), 7.23 (d, 0.5H, J =7Hz), 6.8 (d, 0.5H, J = 8Hz), 6.31 (d, 0.5H, J = 7 Hz), 5.83 (d, 0.5H, J = 8Hz), 4.8 (s, 1H), 4.6-3.8 (m, 4H), 3.6-3.5 (m, 1 H), 3.45-3.3 (m, 2H), 3.0-2.8 (m, 1 H), 1.9-1.58 (m, 5H), 1.48-1.13 ( , 5H).
Example 83
Figure imgf000130_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsuif onyl)-3-(phenylmethyl)-1 H-naphtho[2,3-e]-1 ,4- diazepine, monohydrochloride.
Example 83 was prepared as an offwhite solid from 2,3,4,5- tetrahydro-3-(phenylmethyl)-1 H-naphtho[2,3-e]-1 ,4-diazepine (prepared as described in Example 81) as described in Example 78.
MS (M+H)+ 447
1 H-NMR (CDCI3, 400 MHz) d 8.72 (1H,m), 7.7-7.1 (12H, m), 5.01 (1H, m), 4.43 (1 H, s), 4.41 (1 H, s) 3.62 (1H, m), 3.15 (1 H, m), 2.95 (1 H, m), 2.72 (1 H, m), 2.3 (3H, s).
Example 84
Figure imgf000131_0001
2,2-Dimethyl-N-[2,3,4,5-tetrahydro-1.(1 H-imidazol-4-ylmethyl)-4- (1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8- yl]propanamide, dihydrochloride.
Example 84 was prepared Example 26 and pivaloyl chloride as described for Example 27. MS (M+H)+ 482 1H NMR ( 270 MHz, CD3OD): d 8.88 (d, 1H, J = 20 Hz), 8.05-7.89 (m, 2H),
7.8-7.4 (m, 6.5H), 7.35 (d, 0.5H, J = 7 Hz), 7.22 (d, 0.5H, J = 7 Hz), 7.1 (d, 0.5H, J = 8Hz), 6.6 (d, 0.5H, J = 8Hz), 5.9 (d, 0.5H, J = 8Hz), 4.6 (s, 1 H), 4.5 (m, 2H), 4.22-3.9 (m, 2H), 3.4-3.3 (m, 2H), 3.05-2.85 (q, 1 H), 1.3 (d, 9H, J = 16Hz).
Example 85
Figure imgf000131_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylsu!fonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, monohydrochloride. A. 2,3,4,5-Tetrahydro-4-(1 -naphthalenylsulfonyl)-7-phenyl-
1 H-1 ,4-benzodiazepine
To a solution of Compound B of Example 12 (500 mg, 2.2 mmol) in dichloromethane (20 mL) was added 1-naphthylsulfonyl chloride (500 mg, 2.2 mmol) and triethylamine (0.31 mL, 2.2 mmol). The solution was stirred for 1 h and concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2x30 mL), water (1x30 mL), 1M aqueous potassium hydrogen sulfate (3x30 mL), dried (Na2S04) and concentrated to give 800 mg (88%) of Compound
A a s a white solid. MS (M+H)+ 415.2
B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylsulfonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, monohydrochloride
Example 85 was prepared as an offwhite solid in 83% yield from
Compound A as described for Compound D of Example 1.
MS (M+H)+ 415 1 H-NMR (CD3OD, 270 MHz) d 8.83 (1 H, s), 8.5 (1 H, m), 8.24 (1 H, d, J=8Hz),
8.11 (1 H, J=8 Hz), 7.94 (1H, m), 7.61-7.25 (9H, m), 7.02 (1H, d, J=8 Hz). 4.61 (2H, s), 4.41 (2H, s) 3.52 (2H, m), 3.09 (2H, m).
Example 86
Figure imgf000132_0001
4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(2-naphthalenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Example 86 was prepared as a white solid from D,L-2- naphthylalanine as described for Example 80. MS (M+H)+ 475 1 H-NMR (CD3OD, 400 MHz) d 8.81 (1H, s), 7.84 (4H, m), 7.70 (1H, m), 7.50-
7.25 (5H, m), 6.87 (1H, m), 4.73-4.54 (3H, m), 4.43 (1H, m), 3.73 (1H, m), 3.23 (1H, m), 3.05 (1H, m), 2.93 (1H, m), 2.13 (1H, m), 2.05 (3H, s).
Example 87
Figure imgf000133_0001
4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)- 3-(1-naphthalenylmethyl)-1H-1,4-benzodiazepine, dihydrochloride.
Example 87 was prepared as a white solid from D.L-1- naphthylalanine as described for Example 80. MS (M+H)+ 475 1 H-NMR (CD3OD, 400 MHz) d 8.53 (1 H, s), 7.87 (1 H, m), 7.74 (1 H, m), 7.55-
7.23 (8H, m), 6.74 (1H, m), 4.57-4.43 (2H, m), 4.15 (1H, m), 3.90 (1H, m), 3.83 (1H, m), 3.48 (2H, m), 3.12 (1H, m), 3.00 (1H, m), 2.06 (2H, m), 2.01 (3H, s).
Figure imgf000134_0001
7-(2-Chlorophenyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 2-Chlorobenzeneboronic acid Borane-THF (100 mL, 100 mmol) was slowly added to a mixture of
2-bromochlorobenzene (5.4 mL, 46 mmol) and magnesium (ribbon, 1.12 g, 46 mmol). The flask was placed in a water bath and sonicated overnight. Water (30 mL) was slowly added to destroy excess borane. The aqueous solution was refluxed for 2 hrs. The solvent was evaporated and the residue was neutralized with aq HCl. The aqueous solution was extracted with ether (2x50 mL), dried (Na2Sθ4) and evaporated to afford Compound A (6.24 g,
86%).
B. 7-(2-Chlorophenyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride
Example 88 was prepared as a gray solid in 55% yield from
Compound A and Compound A of Example 37 as described for Example 60.
MS (M+H)+ 493 1 H-NMR (CD3OD, 300MHz) d 2.95 (br m, 1H), 3.30 (m, 1 H), 4.00 (br s, 1 H),
4.20 (br s, 1 H), 4.40 (br d, 1 H), 4.60 (m, 1 H), 4.65(m, 1 H), 5.05 (s, 1 H), 6.05 (d, 1 H), 7.00 (d, 1 H), 7.15-8.10(m, 13H), 8.85 (s, 1 H), 8.95(s, 1 H). Example 89
Figure imgf000135_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, monohydrochloride.
A solution of 2,3,4,5-tetrahydro-4-[(1 ,1-dimethylethoxy)-carbonyl]-7- phenyl-1 H-1 ,4-benzodiazepine (prepared from Compound B of Example 12 as described for Compound A of Example 4, 0.20 g) and 4-formyl imidazole (0.52 g, 5.6 mmol) in CH2CI2 (10 mL) and acetic acid (2 mL) was stirred for
40 min. Sodium triacetoxyborohydride (0.9 g, 6 mmol) was added and stirring was continued for 4 hrs. Sodium bicarbonate (sat., 5 mL) and ammonium hydroxide (cone, 5 mL) were added and the mixture was stirred for another 3 hrs. The aqueous layer was extracted with CH2CI2 (3x50 mL).
The combined organic layers were washed with 1 N NaOH (2x10 mL) and cone. NH4OH (10 mL), dried (Na2SO4) and evaporated. The residual solid was stirred in MeOH (5 mL) and aqueous HCl in dioxane (4 M, 10 mL) overnight. The solvent was evaporated and the residue was triturated with CHCI3 to give a solid (0.35 g) which was purified by preparative HPLC
(methanol/water gradient with 0.1% TFA) and converted to the HCl salt by lyophilization from 1 M HCl (5 mL) to provide Example 89 (0.12 g, 57%) as an off white solid. MS (M+H)+ 305 1 H-NMR (CD3OD): 3.26 (m, 4H), 4.45 (s, 2H), 4.62 (s, 2H), 7.2-7.8 (m, 10H),
8.95 (s, 1 H). Example 90
Figure imgf000136_0001
1 -Methyl-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-2- piperidinecarboxamide, trihydrochloride.
Example 90 was prepared as a light yellow solid from Example 26 and N-methyl-pipecolic acid as described for Example 62. MS (M+H)+ 523 1 H NMR ( 270 MHz, CD3OD): d 8.9 (d, 1 H, J = 22 Hz), 8.08-7.88 (m, 2.5H),
7.7-7.2 (m, 6H), 6.8 (d, 0.5H), 5.9 (m, 0.5H), 5.0 (m, 1.5H), 4.6 (s, 1 H), 4.5 (m, 2H), 4.3-4.1 (m, 1H), 4.05-3.9 (m, 1 H), 3.6-2.7 (m, 8H), 2.3 (t, 1H), 2.05-1.56 (m, 3H), 1.5 -0.8 (m, 3H).
Example 91
Figure imgf000136_0002
N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenyl-carbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-4- morpholinecarboxamide, dihydrochloride. Example 91 was prepared as a light yellow solid from Example 26 and morpholine N-carbonyl chloride as described for Example 27.
MS (M+H)+ 511
1 H NMR (270 MHz, CD3OD): d 8.88 (q, 1H), 8.1-7.88 (m, 2.5H), 7.7-7.3 (m,
6.5H), 7.2 (t, 0.5H), 6.9 (d, 0.5H), 6.5 (d, 0.5H), 5.85 (d, 0.5H), 5.08-4.9 (m, 2H) 4.6-4.15 (m, 4H), 3.7-3.65 (m, 3H), 3.6-3.4 (m, 4H), 3.4-3.28 (m, 2H), 3.15-2.8 (m, 1 H).
Figure imgf000137_0001
N-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenyl-carbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-3- methylbutanamide, dihydrochloride.
Example 92 was prepared as a light yellow solid in 67% yield from Example 26 and isobutyryl chloride as described for Example 27, except that the reaction mixture was concentrated after no starting material was observed, the residue was treated with MeOH and 1N NaOH for 30 min, and after workup, the product was treated with HCI/ether.
MS (M+H)+ 482
1 H NMR ( 270 MHz, CD3OD): d 8.88 (d, 1 H, J = 21 Hz), 8.08-7.9 (m, 2.5H), 7.7-7.19 (m, 6.5H), 6.81 (d, 0.5H), 5.9 (d, 0.5H) 4.9 (m, 1H), 4.6-3.9 (m, 4H), 3.6-3.08 (m, 2H), 3.0-2.76 (m, 4H), 2.3 (m, 1H), 2.05-1.5 (m, 3H) 1.45-0.8 (m, 3H). Example 93
Figure imgf000138_0001
1 ,2,3,4-Tetrahydro-4-[(1 H-imidazol-4-yl)methyl]-1 -(naphthalen-1 - ylsulfonyl)quinoxaiine, dihydrochloride
A. 1 ,2,3,4-Tetrahydro-1 -(naphthalen-1 - ylsulfonyl)quinoxaline To a solution of Compound A of Example 3 ( 270 mg, 2 mmol) in dichloromethane (8 mL) at rt under argon was added triethylamine (0.42 mL, 3 mmol) and naphthalenesulfonyl chloride (500 mg, 2.2 mmol). After 18 hr, the mixture was washed successively with saturated NaHCθ3 and brine (10 mL each), dried (MgS04) and concentrated. Dichloromethane (1mL) was added to the residual yellow solid and Compound A crystallized. The solution was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford additional Compound A, total yield 560 mg, 87%.
MS: (M+H)+ = 325+
B. 1 ,2,3,4-Tetrahydro-4-[(1 H-imidazol-4-yl)methyl]-1 - (naphthalen-l-ylsulfonyl)quinoxaline, dihydrochloride
Example 93 was prepared as a pale yellow solid from Compound A as described for Compound D of Example 1. Purification by flash silica gel column chromatography eluting with 9:1 CHCI3: MeOH afforded a solid which was converted to its HCl salt by treatment 1M HCl in ether (95 mg,
80%).
MS (M+H)+ 405
1 H NMR (free base) (CDCI3) d 8.22 (1 H, d, J = 7.3 Hz), 8.15 (1 H, d, J = 8 Hz), 8.02 (1 H, d, J = 8 Hz), 7.87 (1 H, d, J = 7.3 Hz), 7.49 (2H, t, J = 8 Hz), 7.39 (1 H, s), 7.37 (1 H, s), 7.31 (1 H, t, J = 7.3 Hz), 7.26 (1 H, s), 7.02 (1 H, t, J = 7.3 Hz), 6.65 (1 H, t, J = 7.3 Hz), 6.54 (1 H, d, J = 8.0 Hz), 6.0 (1 H, s), 4.0 (2H, s), 3.83 (2H, t, J = 5.3 Hz), 2.85 3.83 (2H, t, J = 5.3 Hz) Example 94
Figure imgf000139_0001
1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N,7-triphenyl- 4H-1 ,4-benzodiazepine-4-carboxamide, dihydrochloride.
Example 94 was prepared as a slightly pink powder from N,N- diphenylcarbamyl chloride as described for Example 35, mp >200°C. MS (M+H)+ 500 Analysis calculated for C32H29N5O «0.4 H2O »1.0 HCl.
Calc'd: C, 70.75; H, 5.71 N, 12.89; Cl, 6.53 Found: C, 70.89; H, 5.53; N, 12.77; Cl, 6.65.
Example 95
Figure imgf000139_0002
1 ,2,3,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)- 4H-naphtho[2,3-e]-1 ,4-diazepine-4-carboxylic acid, methyl ester, monohydrochloride. Example 95 was prepared as an off white solid from methyl chloroformate as described for Example 83. MS (M+H)+ 427 1 H-NMR(CD3θD, 400 MHz) d 8.72 (1 H,m), 7.7-7.1 (12H, m), 5.01 (1 H, m),
4.43 (1 H, s), 4.41 (1 H, s) 3.62 (1 H, m), 3.15 (1 H, m), 2.95 (1 H, m), 2.72 (1 H, m), 2.6 (3H, s).
Example 96
Figure imgf000140_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(4- phenyl-1 ,2,3-thiadiazol-5-yl)carbonyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 96 was prepared as a white lyophilate in 50% yield from 4-pheny-5-carboxy-1 ,2,3-thiadiazole as described for Example 34, with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA).
MS (M+H)+ 493
Analysis calculated for C28H24N6OS »0.11 H2O -1.6 TFA.
Calc'd: C, 55.35; H, 3.84 N, 12.41 Found: C, 55.28; H, 3.71 ; N, 12.37. Example 97
Figure imgf000141_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(4- phenyl-1 ,2,3-thiadiazol-5-yl)carbonyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 97 was prepared as a white lyophilate in 6% yield from 2,3-methylenedioxy-benzoic acid as described for Example 34, with purification by preparative HPLC (gradient of aqueous methanol with 0.1%
TFA).
MS (M+H)+ 453
1HNMR(CD30D): 3.11 (m, 1 H), 3.61 (m, 1 H), 3.87 (br m, 2 H), 4.61-4.64 (m, 2 H), 5.81 , 6.06 (s, 2 H), 5.96 (s, 2 H), 6.68-7.69 (m, 12 H), 8.42 (m, 1 H), 8.89 (m, 1 H).
Example 98
Figure imgf000142_0001
8-[[(Cyclohexylamino)carbonyl]amino]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine- 4-carboxylic acid,1 ,1-dimethylethyl ester.
A. 2,3,4,5-Tetrahydro-3-(phenylmethyl)-8-nitro-1 H-1 ,4- benzodiazepin-2,5-dione
Compound A was prepared from 7-nitroisatoic anhydride and phenylalanine as described for Compound A of Example 1 , except that after refluxing for 1 day, the mixture was concentrated. Dimethyl acetamide was added and the mixture was heated at 150°C for 4 hr, concentrated and water was added. The olive green solid obtained was filtered and air dried to obtain Compound A in 80 % yield). MS (M+H)+ 312
B. 2,3,4,5-Tetrahydro-3-(phenylmethyl)-8-nitro-1 H-1 ,4- benzodiazepine Borane in THF (1M, 86 mL) was added to Compound A (7.5 g,
24.01 mmol) and the mixture was refluxed for 2 days, cooled to rt, acidified with 3N HCl, and steam heated for 30 min. The solid was filtered and dried to afford Compound B (3.75 g, 95 % ) as an olive green solid. MS (M+H)+ 254. The filtrate was made basic with 5N NaOH (pH 8-9) and extracted with CHCIg, dried over MgSO4, filtered and concentrated to afford 2,3,4,5- tetrahydro-3-(phenylmethyl)-8-amino-1H-1 ,4-benzodiazepine (1.1 g, 21%). C . 8-Nitro-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-4-carboxylic acid,1 ,1-dimethylethyl ester
Boc anhydride (1.5 g, 7 mmol) was added to a solution of Compound B (2.0 g, 7 mmol) and triethylamine (0.71 g, 7 mmol) in THF (30 mL) under argon. After stirring for 6 hr, the mixture was extracted with CHCI3
(3 x 70 mL). The combined extracts were washed with water (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered and concentrated. The residue was triturated with hexane/CHCI3 to afford Compound C as an olive green solid (0.89 g, 34 %). MS (M-H)' 382
D . 8-Nitro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine-4-carboxylic acid,1 ,1 - dimethylethyl ester
Compound D was prepared from Compound C as described for Compound D of Example 1 , with stirring for 15 hours. MS (M+H)+ 464
E. 8-Amino-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-4-carboxylic acid,1 ,1 - dimethylethyl ester 16 % aqueous TiC.3 (2.66 g, in 15 mL H2O, 17.2 mmol) was added to a solution of Compound D (1.0 g, 2.15 mmol) in ACOH/H2O (16 mL, 1 :1). After stirring for 15 min, the mixture was made basic with 5 N NaOH, stirred for 30 min and extracted with 10% isopropanol/CH2CI2. The layers were separated, the aqueous layer was extracted with 10% isopropanol/CH2Cl2 and the combined organic layers were dried over MgSθ4, filtered and concentrated to afford Compound E (0.70g, 75 %). MS (M+H)+ 434-
F. 8-[[(Cyclohexylamino)carbony l]amino]-2, 3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-4-carboxylic acid,1 ,1-dimethylethyl ester
Compound F was prepared from Compound E using the procedure described by Example 27, using cyclohexylisocyanate. The reaction mixture was concentrated and the residue was treated with 1 N NaOH and MeOH. After stirring for 30 min, the mixture was diluted with CHCI3 and NaHCO3. The layers were separated and the aqueous layer was reextracted twice with CHCI3. The combined organic layers were washed with water, brine, dried over MgSθ4, filtered and concentrated to afford Example 98 as a light yellow solid. MS: [M+H]+ = 559+- MS (M+H)+ 559
Example 99
Figure imgf000144_0001
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-8-[[(4- methylphenyl)sulfonyl]amino]-3-(phenyimethyl)-1 H-1 ,4- benzodiazepine-4-carboxylic acid, 1 ,1-dimethylethylester.
p-Toluenesulfonyl chloride (0.054 g, 0.34 mmol) was added to a solution of 8-amino-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine-4-carboxylic acid,1 ,1 -dimethylethyl ester (prepared as described in Compound E of Example 98, 0.125 g, 0.28 mmol) and triethylamine (0.048 mL, 0.34 mmol) in CH2CI2 (1 mL) at 0°C under argon. After stirring for 16 hr, the mixture was concentrated and the residue was treated with 1 N NaOH (0.6 mL) and MeOH (1 mL). After stirring for 30 min, the reaction mixture was diluted with CHCI3 (5 mL) and NaHC03
(3 mL). The layers were separated and the aqueous layer was reextracted with CHCI3 (2 x 20 mL). The combined organic layers were washed with water (1 x 5 mL), brine (1 x 5 mL), dried over MgSθ4, filtered and concentrated to afford Example 99 (0.15 g, 89%) as a light yellow solid. MS (M+H)+ 588 Example 100
Figure imgf000145_0001
7-Bromo-1 ,2,3,4-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-5H-1 ,4-benzodiazepin-5-one, dihydrochloride.
A. 7-Bromo-2,3,4,5-Tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-5-one To a suspension of 0.5 g (1.45 mmoles) of Compound A of
Example 75 in 5 mL of THF at rt and under argon, was added 3 mL (3 mmol) of 1 M borane in THF. A clear, bright yellow solution was obtained on addition. Stirring was continued overnight, after which an additional 2 mL (2 mmol) of 1 M borane in THF was added and stirring was continued an additional 8 hr. After hydrolysis of excess borane by the dropwise addition of methanol, the reaction was evaporated to dryness and the residue dissolved in 0.5 mL each of methanol and cone HCl. The resulting solution was heated at reflux for 2 hr, cooled to rt and evaporated to dryness. The residue was evaporated from methanol an additional three times, dissolved in ethyl acetate and the solution washed with brine, dried, and the solvent removed to afford a viscous yellow oil. Flash chromatography on silica gel. with 50% ethyl acetate - hexane gave 205 mg (0.62 mmole, 43 %) of Compound A as a white solid.
B. 7-Bromo-1 ,2,3,4-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-
3-(phenylmethyl)-5H-1 ,4-benzodiazepin-5-one, dihydrochloride
Example 100 was prepared as a nearly white solid in 60% yield from Compound A as described for Compound D of Example 1 , with purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and conversion to the HCl salt by treatment with HCI-MeOH. MS (M+H)+ 411
Analysis calculated for C2θHl9N4θBr »0.5 C2H10O «1.5 HCl.
Calc'd: C, 52.53; H, 5.11 N, 11.14. Found: C, 52.82; H, 4.71 ; N, 11.52.
Examples 101-201
The coupling of each carboxyiic acid to Compound B of Example 33 was carried out using standard HOAt / DIC mediated coupling. The process was automated by using a Hamilton 2200 Liquid Handler. A Zymark Benchmate® robotic workstation was used to carry out the weighings of the test tubes and for purification of the resulting amide products. An IBM PC was used to run the Zymark Benchmate® workstation operating program and to write the Benchmate® procedures. The standard protocol for preparation of amides is illustrated by the following examples: A 16 x 100 mm tube was charged with the appropriate carboxyiic acid (0.10 mmol, 1.0 eq) and the Liquid Handler then carried out the following steps on the tube: 1) Added 0.5 mL of a 0.2 M 1 -hydroxy-7-aza-benzotriazole (HOAt) solution in DMF
2) Added 0.5 mL of Compound B of Example 33 (0.2 M, 0.10 mmol, 1.0 eq) in DMF
3) Added 1.0 mL of a methylene chloride solution of diisopropylcarbodiimide (0.016 mL, 0.10 mmol, 1.0 eq)
4) Mixed tube contents by vortexing at speed 3 for 30 sec.
After 24 hr, the mixture was concentrated on a Savant Speed Vac (approx. 2 mm Hg for 72 hr). The residue was purified by ion exchange chromatography on a solid phase extraction cartridge mediated by the Benchmate® robotic workstation using the following protocol:
1) Added 5.0 mL of methanol/methylene chloride(1 :1) to the reaction
2) Mixed tube contents by vortexing at speed 3 for 60 sec
3) Conditioned a Varian solid phase extraction column (1.5 g, SCX cation exchange) with 10 mL of methanol/methylene chloride at 0.15 mL/sec 4) Loaded reaction contents onto column at 0.02 rnUsec
5) Washed column with 2 x 7.5 mL of methanol/methylene chloride(1 :1) at 0.1 mL sec 6) Washed column with 1 x 7.5 mL of methanol at 0.1 mLJsec
7) Washed column with 0.01 M ammonia in methanol
8) Eluted column with 7.5 mL of 1 M ammonia in methanol and collect into a tared receiving tube at 0.05 mL/sec. All solution/solvent deliveries were followed by 1.0 mL of air and a 5 sec push delay was used after loading reaction contents onto the ion exchange column. The product solution was concentrated on a Savant Speed Vac (approx. 2 mm Hg for 20 hr) to afford the target compound. Syntheses requiring further purification were subjected to preparative HPLC (YMC S3 ODS 50X100 mm, 30 mL min, 10 minute gradient of 10-90% aqueous methanol with 0.1%TFA, monitored at 220 nm). The appropriate fractions were combined and concentrated under vacuum. The residues were dissolved in methanol (5 mL) and 1N HCl (1 mL) and concentrated on a Savant Speed Vac (approx. 2 mm Hg for 20 hr) to afford the target compound. Target compounds were characterized by analytical HPLC and mass spectrometry.
Example Structure Mass Spectrum
101 2,3,4,5-Tetrahydro-1-(1 H- m/z 444 imidazol-4-ylmethyl)-4-[1 -oxo- (M+H)
3-(1 -piperidinyl)propyl]-7- phenyl-1 H-1 ,4-
Figure imgf000148_0001
benzodiazepine, trihydrochloride.
102 2,3,4,5-Tetrahydro-1 -(1 H- m/z 460 imidazol-4-ylmethyl)-7-phenyl- (M+H)
4-(4-quinolinylcarbonyl)-1 H-
1 ,4-benzodiazepine, trihydrochloride.
103 4-[(5-Bromo-3- m/z 489 pyridinyl)carbonyl]-2,3,4,5- (M+H) tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-
Figure imgf000148_0002
benzodiazepine, trihydrochloride.
104 (S)-4-[2-(Dimethylamino)-1 - m/z 480 oxo-3-phenylpropyl]-2,3,4,5- (M+H) tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-
Figure imgf000148_0003
benzodiazepine, trihydrochloride.
105 2,3,4,5-Tetrahydro-4-[4- m/z 524 hydroxy-3-(4-morpholinyl- (M+H) methyl)benzoyl]-1-(1 H- imidazol-4-ylmethyl)-7-phenyl-
Figure imgf000148_0004
1 H-1 ,4-benzodiazepine, trihydrochloride. 106 (S)-2,3,4,5-Tetrahydro-1 -(1 H- m/z 416 imidazol-4-ylmethyl)- 4-[(1- (M+H) methyl-2-pyrrolidinyl)carbonyl]-
7-phenyl-1 H-1 ,4-
Figure imgf000149_0001
benzodiazepine, trihydrochloride.
107 2,3,4,5-Tetrahydro-1 -(1 H- m/z 484 imidazol-4-ylmethyl)-7-phenyl- (M+H)
4-[[2-(propylthio)-3- pyridinyl]carbonyl]-1 H-1 ,4- benzodiazepine, trihydrochloride.
108 4-[(2-Chloro-6-methyl-4- m/z 458 pyridinyl)carbonyl]-2,3,4,5- (M+H) tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-
Figure imgf000149_0002
benzodiazepine, trihydrochloride.
109 2,3,4,5-Tetrahydro-1-(1 H- m/z 518 imidazol-4-ylmethyl)-7-phenyl- (M+H)
4-[[2-(phenylthio)-3- pyridinyl]carbonyl]-1 H-1 ,4-
Figure imgf000149_0003
benzodiazepine, trihydrochloride. 10 2,3,4,5-Tetrahydro-1-(1 H- m/z 516 imidazol-4-ylmethyl)-4-[[2-(4- (M+H) methylphenoxy)-3- pyridinyl]carbonyl]-7-phenyl-
1 H-1 ,4-benzodiazepine, trihydrochloride. 1 1 2,3,4,5-Tetrahydro-1 -(1 H- m/z 440 imidazol-4-ylmethyl)-4-[(2- (M+H) methoxy-3-pyridinyl)carbonyl]-
7-phenyl-1 H-1 ,4-
Figure imgf000149_0004
benzodiazepine, trihydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H- m/z 476 imidazol-4-ylmethyl)-7-phenyl- (M+H)
4-[(5-phenyl-4- oxazolyl)carbonyl]-1 H-1 ,4- benzodiazepine, dihydrochloride.
4-Acetyl-2,3,4,5-tetrahydro-1- m/z 347
(1 H-imidazol-4-ylmethyl)-7- (M+H) phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H- m/z 403 imidazol-4-ylmethyl)-7-phenyl- (M+H)
4-[(tetrahydro-3- furanyl)carbonyl]-1 H-1 ,4-
Figure imgf000150_0001
benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H- m/z 421 imidazol-4-ylmethyl)-4-[(2- (M+H) methoxyethoxy)acetyl]-7- phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H- m/z 508 imidazol-4-ylmethyl)-4-[4-(4- (M+H) morpholinylmethyl)benzoyl]-7- phenyl-1H-1 ,4- benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H- m/z 487 imidazol-4-ylmethyl)-4-[4- (M+H)
(methylsulfonyl)benzoyl]-7- phenyl-1H-1 ,4-
Figure imgf000150_0002
benzodiazepine, dihydrochloride. 2,3,4,5-Tetrahydro-1-(1 H- m/z 501 imidazol-4-ylmethyl)-4-[1 -oxo- (M+H) 3-(phenylsulfonyl)propyl]-7- phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride. 2,3,4,5-Tetrahydro-1-(1 H- m/z 424 imidazol-4-ylmethyl)-7-phenyl- (M+H) 4-(3-pyridinylacetyl)-1 H-1 ,4- benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H- m/z 461 imidazol-4-ylmethyl)-7-phenyl- (M+H) 4-(2-quinoxalinylcarbonyl)-1 H- 1 ,4-benzodiazepine, tetrahydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H- m/z 460 imidazol-4-ylmethyl)-4-(4- (M+H) isoquinolinylcarbonyl)-7- phenyl-1 H-1 ,4- benzodiazepine, trihydrochloride. 4-[(2-Chloro-3- m/z 444 pyridinyl)carbonyl]-2,3,4,5- (M+H) tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-
Figure imgf000151_0001
benzodiazepine, trihydrochloride. 2,3,4,5-Tetrahydro-1-(1 H- m/z 410 imidazol-4-ylmethyl)-7-phenyl- (M+H)
4-(3-pyridinylcarbonyl)-1 H-1 ,4- benzodiazepine,
Figure imgf000151_0002
trihydrochloride. 4-[(2,6-Dimethoxy-3- m/z 470 pyridinyl)carbonyl]-2,3,4,5- (M+H) tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-
Figure imgf000152_0001
benzodiazepine, trihydrochloride.
125 m/z 411 (M+H) -
126 m/z 453 (M+H)
127 m/z 452 (M+H)
128 m/z 449 (M+H)
Figure imgf000152_0002
dihydrochloride.
129 4-[(Bicyclo[4.2.0]octa-1 ,3,5- m/z 435 trien-7-yl)carbonyl]-2,3,4,5- (M+H) tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-
Figure imgf000152_0003
benzodiazepine, dihydrochloride. 130 4-Benzoyl-2,3,4,5-tetrahydro-1 -m/z 409
(1 H-imidazol-4-ylmethyl)-7- (M+H) ρhenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
131 4-(2-Chlorobenzoyl)-2,3,4,5- m/z 443 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
132 4-(2,3-Dichlorobenzoyl)- m/z 478
2,3,4,5-tetrahydro-1 -(1H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
133 N-[2-[[2,3,4,5-Tetrahydro-1- m/z 466
(1 H-imidazol-4-ylmethyl)-7- (M+H) phenyl-1 H-1 ,4-benzodiazepin-
4-yl]carbonylJphenyl]- acetamide, dihydrochloride. 34 2,3,4,5-Tetrahydro-1-(1 H- m/z 501 imidazol-4-ylmethyl)-4-(2- (M+H) phenoxybenzoyl)-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride. 35 2,3,4,5-Tetrahydro-1-(1 H- m/z 439 imidazol-4-ylmethyl)-4-(2- (M+H) methoxybenzoyl)-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride. 36 4-(2,3-Dimethoxybenzoyl)- m/z 469
2,3,4,5-tetrahydro-1-(1 H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine,
Figure imgf000153_0001
dihydrochloride. 4-(2,4-Dimethoxybenzoyl)- m/z 469
2,3,4,5-tetrahydro-1-(1H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
4-(2,5-Dimethoxybenzoyl)- m/z 469
2,3,4,5-tetrahydro-1-(1 H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
4-(2,6-Dimethoxybenzoyl)- m/z 469
2,3,4,5-tetrahydro-1-(1H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
4-(2,3-Dihydroxybenzoyl)- m/z 439
2,3,4,5-tetrahydro-1-(1 H- (M-H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
4-([1 , 1 '-Biphenyl)-2- m/z 485 ylcarbonyl)-2,3,4,5-tetrahydro- (M+H)
1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H- m/z 423 imidazol-4-ylmethyl)-4-(2- (M+H) methylbenzoyl)-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride.
4-(2,3-Dimethylbenzoyl)- m/z 437
2,3,4,5-tetrahydro-1-(1H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine,
Figure imgf000154_0001
dihydrochloride. 144 4-(3-Cyanobenzoyl)-2,3,4,5- m/z 434 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
145 4-(3-Chlorobenzoyl)-2,3,4,5- m/z 443 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
146 2,3,4,5-Tetrahydro-1-(1 H- m/z 501 imidazol-4-ylmethyl)-4-(3- (M+H) phenoxybenzoyl)-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride.
147 2,3,4,5-Tetrahydro-1-(1 H- m/z 439 imidazol-4-ylmethyl)-4-(3- (M+H) methoxybenzoyl)-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride.
148 4-(3,4-Dimethoxybenzoyl)- m/z 469
2,3,4,5-tetrahydro-1 -(1 H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
149 4-(3,5-Dimethoxybenzoyl)- m/z 469
2,3,4,5-tetrahydro-1 -(1 H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
150 2,3,4,5-Tetrahydro-1 -(1 H- m/z 423 imidazol-4-ylmethyl)-4-(3- (M+H) methylbenzoyl)-7-phenyl-1 H-
1 ,4-benzodiazepine,
Figure imgf000155_0001
dihydrochloride. 151 4-( 1 ,2-Dioxo-2-phenylethyl)- m/z 437
2,3,4,5-tetrahydro-1 -(1 H- (M+H) imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
152 4-[(2-Ethoxy-1- m/z 503 naphthalenyl)carbonyl]-2,3,4,5-(M+H) tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
153 2,3,4,5-Tetrahydro-1 -(1 H- m/z 459 imidazol-4-ylmethyl)-4-(2- (M+H) naphthalenylcarbonyl)-7- phenyM H-1 ,4- benzodiazepine, dihydrochloride.
154 4-(Fluorophenylacetyl)-2,3,4,5- m/z 441 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
155 4-(Diphenylacetyl)-2,3,4,5- m/z 499 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
156 2,3,4,5-Tetrahydro-4-(2- m/z 453 hydroxy- 1 -0X0-2- (M+H) phenylpropyl)-1-(1 H-imidazol- 4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
157 2,3,4,5-Tetrahydro-1-(1 H- m/z 448 imidazol-4-ylmethyl)-4-(1 H- (M+H) indol-2-ylcarbonyl)-7-phenyl- 1 H-1.4- benzodiazepine,
Figure imgf000156_0001
dihydrochloride. 158 2,3,4,5-Tetrahydro-1 -(1 H- m/z 448 imidazol-4-ylmethyl)-4-(1 H- (M+H) indol-3-ylcarbonyl)-7-phenyl- 1 H-1 ,4- benzodiazepine, dihydrochloride.
159 2,3,4,5-Tetrahydro-1-(1 H- m/z 448 imidazol-4-ylmethyl)- 4-(1 H- (M+H) indol-5-ylcarbonyl)-7-phenyl- 1 H-1 ,4-benzodiazepine,
Figure imgf000157_0001
dihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-m/z 462 imidazol-4-ylmethyl)-4- (M+H)
[(1 -methyl- 1 H-indol-2- yl)carbonyl]-7-phenyl-1 H-
Figure imgf000158_0001
1 ,4-benzodiazepine, dihydrochloride.
Figure imgf000158_0002
benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-m/z 426 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-(3- pyridinylcarbonyl)-1 H-
Figure imgf000158_0003
1 ,4-benzodiazepine, N- oxide, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-m/z 410 imidazol-4-yimethyl)-7- (M+H) phenyl-4-(2- pyridinylcarbonyl)-1 H-
Figure imgf000158_0004
1 ,4-benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-m/z 460 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-(2- quinolinylcarbonyl)-1 H-
Figure imgf000158_0005
1 ,4-benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-m/z 460 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-(1 - isoquinolinylcarbonyl)-
Figure imgf000158_0006
1 H-1 ,4-benzodiazepine, trihydrochloride. 166 4-(3-Chloro-2- m/z 488 nitrobenzoyl)-2,3,4,5- (M+H) tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000159_0001
phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
167 2,3,4,5-Tetrahydro-1-(1 H-m/z 454 imidazol-4-ylmethyl)-4-(2-(M+H) nitrobenzoyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride.
168 2,3,4,5-Tetrahydro-1-(1 H-m/z 484 imidazol-4-ylmethyl)-4-(3-(M+H) methoxy-2-nitrobenzoyl)-
7-phenyl-1 H-1 ,4-
Figure imgf000159_0002
benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-m/z 448 imidazol-4-ylmethyl)-4- (M+H)
(1 H-indol-4-ylcarbonyl)-
7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
4-[(2,6-Dihydroxy-3- m/z 491 naphthalenyl)carbonyl]- (M+H)
2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000159_0003
phenyl-1H-1 ,4- benzodiazepine, dihydrochloride. 4-(1H-Benzimidazol-5- m/z 449 ylcarbonyl)-2,3,4,5- (M+H) tetrahydro-1-(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000160_0001
phenyl-1 H-1 ,4- benzodiazepine, trihydrochloride.
4-(1 H-Benzotriazol-5- m/z 450 ylcarbonyl)-2,3,4,5- (M+H) tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000160_0002
phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
173 2,3,4,5-Tetrahydro-1 -(1 H-m/z 490 imidazol-4-ylmethyl)-4- (M+H)
[(4-methoxy-2- quinolinyl)carbonyl]-7-
Figure imgf000160_0003
phenyl-1 H-1 ,4- benzodiazepine, trihydrochloride.
174 N-[3-[[2,3,4,5-Tetrahydro- m/z 466
1 -(1 H-imidazol-4- (M+H) ylmethyl)-7-phenyl-1 H-
1 ,4-benzodiazepin-4-
Figure imgf000160_0004
yl]carbonyl]phenyl]- acetamide, dihydrochloride.
175 2,3,4,5-Tetrahydro-1 -(1 H-m/z 451 imidazol-4-ylmethyl)-4-(2-(M+H) methyl-1 -oxo-2- phenylpropyl)-7-phenyl-
Figure imgf000160_0005
1 H-1 ,4-benzodiazepine, dihydrochloride.
Figure imgf000161_0001
benzodiazepine, trihydrochloride.
4-(3-Ethoxybenzoyl)- m/z 453 2,3,4,5-tetrahydro-1-(1 H- (M+H) imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-
Figure imgf000161_0002
benzodiazepine, dihydrochloride.
178 2,3,4,5-Tetrahydro-4-(2- m/z 501 hydroxy[1 ,1 '-biphenyl]-3- (M+H) ylcarbonyl)-1 -(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000161_0003
phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
179 5
Figure imgf000161_0004
1 ,4-benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-m/z 489 imidazol-4-ylmethyl)-4- (M+H) [(2-methoxy-1 - naphthalenyl)carbonyl]-7-
Figure imgf000161_0005
phenyl-1H-1 ,4- benzodiazepine, dihydrochloride. 2,3,4,5-Tetrahydro-4-[(2- m/z 476 hydroxy-4-quinolinyl)- (M+H) carbonyl]-1 -(1 H-imidazol- 4-ylmethyl)-7-phenyl-1 H- 1 ,4-benzodiazepine, dihydrochloride. 2-[[2,3,4,5-Tetrahydro-1- m/z 452
(1 H-imidazol-4-ylmethyl)- (M+H) 7-phenyl-1 H-1 ,4- benzodiazepin-4-
Figure imgf000162_0001
yl]carbonyl]benzamide, dihydrochloride. N-(1 ,1-Dimethylethyl)-2- m/z 508
[[2,3,4,5-tetrahydro-1- (M+H) (1 H-imidazol-4-ylmethyl)- 7-phenyl-1 H-1 ,4-
Figure imgf000162_0002
benzodiazepin-4- yl]carbonyl]benzamide, dihydrochloride. N-(4-Fiuorophenyl)-N'-[3- m/z 561 [[2,3,4,5-tetrahydro-1- (M+H) (1 H-imidazol-4-ylmethyl)- 7-phenyl-1 H-1 ,4-
Figure imgf000162_0003
benzodiazepin-4- yl]carbonyl]phenyl]urea, dihydrochloride. 2,3,4,5-Tetrahydro-1-(1 H-m/z 567 imidazol-4-ylmethyl)-4- (M+H) [(3-methyl-4-oxo-2- phenyl-4H-benzopyran-
Figure imgf000162_0004
8-yl)carbonyl]-7-phenyl- 1 H-1 ,4-benzodiazepine, dihydrochloride. 186 2,3,4,5-Tetrahydro-1 -(1 H-m/z 493 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-[3-
(trifluoromethoxy)benzoyl
]-1 H-1 ,4-benzodiazepine, dihydrochloride.
187 4-(2-Cyanobenzoyl)- m/z 434
2,3,4,5-tetrahydro-1-(1 H- (M+H) imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-
Figure imgf000163_0001
benzodiazepine, dihydrochloride.
188 ro-1-(1 H-m/z 578 hyl)-4-[2-(M+H)
lfonyl]am
Figure imgf000163_0002
benzoyl]-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride.
189 2,3,4,5-Tetrahydro-1 -(1 H-m/z 460 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-(6- quinolinylcarbonyl)-1 H-
Figure imgf000163_0003
1 ,4- benzodiazepine, trihydrochloride.
190 2,3,4,5-Tetrahydro-1-(1 H-m/z 460 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-(8- quinolinylcarbonyl)-1 H-
Figure imgf000163_0004
1 ,4-benzodiazepine, trihydrochloride. 4-(Benzo[b]thiophen-2- m/z 465 ylcarbonyl)-2,3,4,5- (M+H) tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000164_0001
phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
192 4-[[4-(Dimethylamino)-1- m/z 502 naphthalenyljcarbonyl]- (M+H)
2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-7-
Figure imgf000164_0002
phenyl-1 H-1 ,4- benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-m/z 449 imidazol-4-ylmethyl)-7- (M-H) phenyl-4-(1 H-purin-6- ylcarbonyl)-1 H-1 ,4-
Figure imgf000164_0003
benzodiazepine, trihydrochloride.
194 2,3,4,5-Tetrahydro-1-(1 H-m/z 453 imidazol-4-ylmethyl)-4- (M+H)
(methoxyphenylacetyl)-7- phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride.
195 2,3,4,5-Tetrahydro-1-(1 H-m/z 489 imidazol-4-ylmethyl)-4- (M+H)
[(5-methyl-1-phenyl-1 H- pyrazol-4-yl)carbonyl]-7-
Figure imgf000164_0004
phenyl-1 H-1 ,4- benzodiazepine, trihydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H-m/z 451 imidazol-4-ylmethyl)-4-[2- (M+H)
(2-methylphenyl)-1 - oxopropyl]-7-phenyl-1 H-
1 ,4-benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-m/z 493 imidazol-4-ylmethyl)-7- (M+H) phenyl-4-[(tetrahydro-4- phenyl-2H-pyran-4-
Figure imgf000165_0001
yl)carbonyl]-1 H-1 ,4- benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-m/z 531 imidazol-4-ylmethyl)-4-[2-(M+18)
(methylphenylamino)ben zoyl]-7-phenyl-1 H-1 ,4-
Figure imgf000165_0002
benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-m/z 476 imidazol-4-ylmethyl)-7- (M+H) phenyi-4-(4- quinolinylcarbonyl)-1 H-
1 ,4-benzodiazepine, N- oxide, dihydrochloride.
N-Methyl-N-(2- m/z 557 pyridiny!methyl)-2- (M+H)
[[2,3,4,5-tetrahydro-1-
(1 H-imidazol-4-ylmethyl)-
Figure imgf000165_0003
7-phenyl-1 H-1 ,4- benzodi-azepin-4- yl]carbonyl]benzamide, trihydrochloride. 201 2,3,4,5-Tetrahydro-1-(1 H-m/z 460 imidazol-4-ylmethyl)-4-(3-(M+H) isoquinolinylcarbonyl)-7- phenyl-1 H-1 ,4-
Figure imgf000166_0001
benzodiazepine, trihydrochloride.
Examples 202-219
To a mixture of compound Compound A of Example 4 (3.83 g, 15.4 mmol) and 4-imidazolecarboxaldehyde (2.22g, 23.1 mmol) in 120 mL of CH2CI2 and 3 mL of AcOH at room temperature was added NaBH(OAc)3 (4.89 g,
23.1 mmol). The mixture was stirred for 1.5 hours, diluted with 200 mL of CH2CI2, and washed with 5% NaHC03. The organic phase was dried over Na2Sθ4, filtered and concentrated in vacuo. Flash chromatography of the residue on silica (eluting with 5% MeOH/CH2Cl2 and trace NH4OH) afforded 2.01 g (40%) of 2,3,4,5-tetrahydro-4-[(1 ,1 -dimethylethoxy)- carbonyl]-1 -(1 H-imidazol-4-yl-methyl)-1 H-1 ,4-benzodiazepine. An additional 0.42 g (8%) of product was obtained by stirring 1.5 g of a high Rf material in 1 :1 :1 THF/MeOH/NH4θH, followed by extraction with EtOAc, and flash chromatography. Hydroxymethyl resin (3.5 g, 6.58 mmol, 1.88 mmol/g) was swelled with 50 mL of 1 ,2-dichloroethane for 45 min at room temperature in a 125 mL shake flask. To this was added paraformaldehyde (0.15 g, 5.0 mmol). HCl (g) was bubbled through the mixture for 15 min. Then, an additional amount of paraformaldehyde (0.15 g, 5.0 mmol) was added to the reaction mixture. HCl (g) was bubbled through the mixture with shaking for 4h. The 1 ,2- dichloroethane was removed and the resin was rinsed with 1 ,2- dichloroethane (4 x 20 mL).
The resin was suspended in 20 mL of 1 ,2-dichloroethane and then treated with a solution of 2,3,4,5-tetrahydro-4-[(1 ,1-dimethylethoxy)-carbonyl]-1 -(1 H- imidazol-4-yl-methyl)-1 H-1 ,4-benzodiazepine (2.23 g, 6.78 mmol) in 25 mL of 1 ,2,dichloroethane and 6 mL of DIEA. The mixture was shaken at room temperature for 12 h. MeOH (2 mL) was added and the mixture was shaken for an additional 1.5 h. The solvent was removed and the resin was rinsed sequentially with 1 ,2-dichloroethane (2 x 20 mL), DMF (2 x 20 mL), and MeOH (2 x 20 mL). The material was dried in vacuo to afford 4.58 g (67%) of resin containing imidazole-bound 2,3,4,5-tetrahydro-4-[(1 ,1-dimethylethoxy)- carbonyl]-1 -(1 H-imidazol-4-yl-methyl)-1 H-1 ,4-benzodiazepine (%N=4.39). To 150 mg (0.135 mmol, 0.90 mmol/g) of this resin in a 5 mL polypropylene syringe barrel was added 1.5 mL of 3% Et3SiH in CH2CI2 and 0.5 mL of TFA. The tube was placed in a vac-elute chamber (capacity for 24 syringe barrels) and the entire apparatus was shaken on an orbital shaker for 3 h. The solvent was removed and the resin was rinsed sequentially with 2 mL each of CH2CI2, 25% Et3N/CH2Cl2, MeOH, DMF, and CH2CI2. The resin was swelled with 0.5 mL of a DMF solution containing 1M DIEA and 0.5M HOBT. To this was added 50 mg of carboxyiic acid, followed by 1.5 mL of a CH2CI2 solution containing 0.2M EDC. The mixture was shaken for 18 h.
The solvent was removed and the resin was rinsed sequentially with 2 mL each of CH2CI2, 25% Et3N/CH2Cl2, MeOH, DMF, and CH2CI2. The coupling procedure was repeated. The products were cleaved from the resin by shaking for 18 h in the presence of a HBr/TFA/thioanisole solution (prepared by mixing 45 mL of TFA, 1.25 mL of thioanisole, and 5 mL of 30% HBr/HOAc). The solvent was removed and the resin was rinsed with MeOH (3 x 3 mL). The solvent was removed in vacuo, and the residue was purified by HPLC (C18, 50 x 100mm, 10%-90% MeOH with 0.1% TFA, 10 min gradient, 20 mL/min). Target compounds were characterized by analytical HPLC and mass spectrometry.
ExampleStructure Mass Spectrum
202 ro-1 -(1 H- m/z 429 hyl)-4-[(2- (M+H) )acetyl]-1 H-1 ,4- trifluoroacetate
Figure imgf000168_0001
203 m/z 421 (M+H)
204 m/z 423 (M+H)
205 m/z 397 (M+H)
Figure imgf000168_0002
206 m/z 409 (M+H)
Figure imgf000169_0001
207 2,3,4,5-Tetrahydro-1-(1 H- m/z 460 imidazol-4-ylmethyl)-4-[(2-phenyl-(M+H)
4-quinolinyl)carbonyl]-1 H-1 ,4- benzodiazepine, trifluoroacetate
Figure imgf000169_0002
(1 :3).
208 m/z 348 (M+H)
cetate
Figure imgf000169_0003
209 lacetyl)-2,3,4,5- m/z 435 midazol-4- (M+H)
rifluoroacetate
Figure imgf000169_0004
210 CWral (S)-4-[2-(Dimethylamino)- 1-oxo- m z 404 3-phenylpropyl]-2,3,4,5- (M+H) tetrahydro-1-(1H-imidazol-4- ylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate (1 :3).
211 (S)-2,3,4,5-Tetrahydro-1-(1H- m/z 432 imidazol-4-ylmethyl)-4-[(2-oxo-4- (M+H) phenyl-3-oxazolidinyl)acetyl]-1 H- 1 ,4-benzodiazepine,
Figure imgf000169_0005
trifluoroacetate (1:2).
212 5- m/z 434 (M+H)
ate
Figure imgf000169_0006
213 m/z 425 (M+H)
cetate
Figure imgf000170_0001
214 2,3,4,5-Tetrahydro-1-(1 H- m/z 477 imidazol-4-ylmethyl)-4-[[4'- (M+H)
(trifluoromethyl)[1 , 1 '-biphenyl]-2- yl]carbonyl]-1 H-1 ,4-
Figure imgf000170_0002
benzodiazepine, trifluoroacetate
(1 :2).
215 m/z 425 (M+H)
cetate
216 m/z 383 (M+H) -1 ,4- cetate
217 m/z 375 xo-4- (M+H)
cetate
Figure imgf000170_0003
218 m/z 439 (M+H)
e
219 m/z 471 (M+H)
Figure imgf000170_0004
220 2,3,4,5-Tetrahydro-1-(1 H- m/z 438 imidazol-4-ylmethyl)-4-[2- (M+H)
[(phenylmethyl)amino]benzoyl]- 1 H-1 ,4-benzodiazepine,
Figure imgf000171_0001
trifluoroacetate (1 :3)
Example 221
Figure imgf000171_0002
1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-N,N-diphenyl- 4H-1 ,4-benzodiazepine-4-carboxamide, hydrochloride.
Example 221 was prepared as a light yellow solid from N,N- diphenylcarbamyl chloride as described for Example 9. MS (M+H)+ 424
Analysis calculated for C-26H25N5O «2.2 H2O »2.2 HCl.
Calc'd: C, 57.47; H, 5.87 N, 12.89; Cl, 14.35 Found: C, 57.25; H, 5.78; N, 13.25; Cl, 14.73.
. Example 222
Figure imgf000171_0003
1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-a,7-diphenyl-4H- 1 ,4-benzodiazepine-4-acetic acid, methyl ester, hydrochloride. To a stirred suspension of Compound B of Example 12 (220 mg, 1.0 mmol) in MeOH in the presence of solid K2CO3 at room temperature under argon was added methyl bromophenylacetate (0.18 mL, 1.1 mmol). The mixture was stirred for 18 h, the solvent was removed, and the residue was purified by flash column chromatography (3:2, hexanes and ethyl acetate) to give 1 ,2,3,5-tetrahydro-a,7-diphenyl-4H-1 ,4-benzodiazepine-4- acetic acid, methyl ester as an oil (220 mg, 63%). This material was reacted as described for Compound D of Example 1 to afford Example 222 as a yellow solid. MS (M+H)+ 453
Analysis calculated for C28H28 4O2 *0.2 H2O »2.5 HCl.
Calc'd: C, 61.44; H, 5.69 N, 10.24; Cl, 16.19. Found: C, 61.33; H, 5.88; N, 9.94; Cl, 16.00.
Example 223
Figure imgf000173_0001
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, hydrochloride.
Example 223 was prepared as a tan solid from isatoic anhydride and D,L-phenylalanine-O methyl ester hydrochloride as described for Example 71 , except that acetyl chloride (0.25 eq) was used in place of napthoyl chloride. MS (M + H)+ 453 Analysis calculated for C22H24N4O • 1.5 H2O -1.2 HCl.
Calc'd: C, 61.74; H, 6.26; N, 13.26; Cl, 9.49. Found: C, 61.80; H, 6.62; N, 13.10; Cl, 9.12.
Example 224
Figure imgf000173_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. A. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-2,5-dione
A stirred solution of bromoisatoic anhydride (150 g, 0.62 mol) and D-phenylalanine methyl ester hydrochloride (127.3 g, 0.59 mol) in the presence of 4-dimethylaminopyridine (2 g) in pyridine (1500 mL) was heated at reflux under argon for 3 days. The pyridine was removed in vacuo and the residue was dissolved in methylene chloride (3 L). This solution was washed with 10% HCl solution and brine. The organic solution was dried and concentrated in vacuo to a small volume. The solid thus formed was collected and dried to give 152 g (71%) of Compound A, mp 242-243°C.
B. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
A stirred solution Compound A (30 g, 87 mmol) in anhydrous THF (870 mL) under argon was treated with a solution of borane-tetrahydrofuran complex (440 mL of a 1 M solution, 440 mmol) at room temperature. The solution was slowly heated to reflux and heated at reflux for 18 h. The mixture was cooled to 0°C, and methanol (150 mL) was added to destroy excess of BH3. The resultant solution was concentrated in vacuo, the residue was dissolved in methanol (250 mL), and 7 N HCl solution (50 mL) was added. This mixture was heated on a steam-bath for 2 h. The solid thus formed was collected, resuspended in water (400 mL) and the aqueous suspension was made basic to pH 11 with 5 N NaOH solution and extracted with ethyl acetate ( 2 x 300 mL). The organic extracts were combined, dried, concentrated in vacuo and the residue was crystallized from methanol and water (9:1) to give 25 grams of Compound B as a white solid (91%), mp 135- 138 °C.
C . (R)-7-Bromo-2,3,4,5-tetrahydro-4-(methylsulf ony l)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
To a stirred solution of Compound B (1.5 g, 4.73 mmol), pyridine (3 mL), and DIEA (1.6 mL, 9.46 mmol) was added methanesulfonyl chloride (0.55 mL, 7.11 mmol) at 0°C under argon. The resultant mixture was stirred at 0°C for 2 h and 1 N NaOH solution (30 mL) was added. The mixture was stirred for 2 hours and the organic layer was separated, washed with 1 N HCl solution (2 x 100 mL), dried, and concentrated in vacuo to give 1.7 g of Compound C as a yellow solid (91 %). D . (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride To a stirred solution of Compound C (18 g, 45.6 mmol) in acetic acid (50 mL) and dichloroethane (200 mL) at room temperature, was added 4-formylimidazole (6.6 g, 68.5 mmol). The mixture was stirred at room temperature for 30 min. To the resultant solution was added sodium triacetoxyborohydride (14.5 g, 68.5 mmol). The mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate (500 mL), cooled to 0°C and made basic to pH 9 with concentrated NH40H solution. The mixture was stirred for 2 h and partitioned between ethyl acetate and saturated NaHC03 solution. The organic layer was separated and washed with saturated NH4CI solution, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized from methanol to give a white solid (14 g, 65%). The solid was dissolved in ethyl acetate and 1 N HCl solution in ether (60 mL) was added. The solvent was removed in vacuo and the solid was dried in a heated oven under vacuum to give Example 224 as a white solid, mp 180-185 °C. MS (M+H)+ 476
[a]D20: +58° (c = 0.4, MeOH).
Example 225
Figure imgf000175_0001
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitriie, monohydrochloride. A. (R)-2,3,4,5-Tetrahydro-4-(methylsulfonyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile
A stirred solution of Compound C of Example 224 (6.9 g, 17.5 mmol) and copper cyanide (4.0 g, 44 mmol) in N-methylpyrrolidinone (90 mL) was heated at 200°C for 5 h. The mixture was cooled to room temperature and poured into a 10% aqueous solution of ethylene diamine (800 mL). The resultant suspension was stirred at room temperature for 2 h and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with 5% NH4OH solution (2 x 100 mL), brine, dried over MgS04, and concentrated. The residue was purified by flash chromatography (ethyl acetate, hexanes; 1 :1) to give Compound A as a foam (4.5 g, 75%).
B. (R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4- (methylsulf onyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitrile, monohydrochloride
To a stirred solution of Compound A (4.7 g, 13.8 mmol) in acetic acid (30 mL) and dichloroethane (120 mL) at room temperature was added 4-formylimidazole (2.1 g, 22 mmol). The mixture was stirred at room temperature for 30 min. To the resultant solution was added sodium triacetoxyborohydride (4.4 g, 22 mmol). The mixture was stirred at room temperature for 2 h, 4-formylimidazole (1.3 g, 13.5 mmol) was added, the mixture was stirred for 30 min, and sodium triacetoxyborohydride (3.0 g, 14 mmol) was added. This cycle was repeated two times until all starting material was consumed. Workup and product isolation were performed as described for Compound D of Example 224 to provide Example 225 as a white solid (4.1 g, 65%). mp 165°C MS (M+H)+ 422 [a]D20: + 218 ° (c = 0.23, MeOH). Analysis calculated for C-22H23 5O2S »1.7 H2O »1 HCl.
Calc'd: C, 54.08; H, 5.65; N, 14.33; Cl, 7.26. Found: C, 54.04; H, 5.38; N, 14.33; Cl, 7.27. Example 226
Figure imgf000177_0001
(R)-4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-3-(phenyimethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. 2-Amino-5-phenyl-benzoic acid 2-Amino-5-bromo-benzoic acid (30.0 g, 139 mmol), benzeneboronic acid (18.6 g, 153 mmol) and K2CO3 (48.0 g, 348 mmol) were combined in a mixture of water (300 mL) and THF (300 mL). The mixture was bubbled with Ar vigorously for an hour to degas and a solution of Palladium(ll) acetate (2.52 g, 11.2 mmol) in degassed THF (50 mL) was added dropwise over 1 h. The mixture was stirred for 16h at room temperature with Ar bubbling. The mixture was concentrated, filtered through a pad of celite and lyophilized to remove water. The lyophiiate was triturated with 90% dichloromethane, 10% methanol (500 mL). The filtrate was concentrated and recrystallized from ethyl acetate/hexane to yield Compound A as a brown solid (25g, 84%), MS (M+H)+ 214.
B. 6-Phenyl-3,1 -oxazine-2,4(1 H)-dione
To a solution of Compound A (25.0 g, 0.117 mol) and triphosgene (25.0 g, 0.084 mol) in acetonitrile (250 mL) at 0°C under N2 was added a solution of triethylamine (3.0 g, 4.1 mL, 0.029 mol) in acetonitrile(50 mL) dropwise over 1 hour. The mixture was stirred at room temperature for 16h and the solid was filtered. The filter cake was washed with dichloromethane and dried under vacuum to yield Compound B as a light brown solid (17.8 g, 63%), MS (M+H)+ 241. C . (R)-2,3,4,5-tetrahydro-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-2,5-dione
Compound B (9.40 g, 0.0392 mol), D-Phe (6.5 g, 0.0392 mol) and pyridineΗCI (22.6 g, 0.196 mol) were dissolved in pyridine (100 mL). The solution was refluxed for 4h, cooled and concentrated. The residue was partitioned between water (200 mL) and ethyl acetate (200mL). The organic layer was washed with water (3X100mL), brine (50 mL), dried (MgSO^ and concentrated to yield compound C as a yellowish glass (6.0 g, 45 %), MS (M+H)+ 343.
D . (R)-2,3,4,5-tetrahydro-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
Compound C (6.0 g, 0.017 mol) was dissolved in THF (100 mL) and borane (1M in THF, 50 mL, 50 mmol) was added. The solution was refluxed for 4h and cooled to room temperature. Methanol (50 mL) was added to quench the residual borane and the solution was concentrated. 1 N HCl (100 mL) was added to the residue and the mixture was refluxed for 4h. The mixture was cooled to room temperature, acidified to pH 2 with 1 N NaOH (110 mL) and extracted with dichloromethane (3X200 mL). The organic layers were combined, washed with brine (300 mL), dried (Na2Sθ4) and concentrated to yield compound D as a slightly yellow glass (5.5 g, 99%), MS (M+H)+ 315.
E . (R)-4-Acetyl-2,3,4,5-tetrahydro-7-phenyl-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine
Compound D (5.0 g, 0.016 mol) was dissolved in dichloromethane (300 mL) and DIEA (2.06 g, 2.8 mL, 0.016 mol) was added at once. A solution of acetic anhydride (1.46 g, 1.35 mL, 0.0143 mol) in dichloromethane (20 mL) was added dropwise over 30 min. The solution was stirred for 30 min, washed with saturated sodium bicarbonate (3X100 mL), water (3X100 mL), brine (100 mL), dried (Na2S04) and concentrated to yield Compound E as a light brown glass (5.0 g, 88%). F. (R)-4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride
Compound E (5.0 g, 14.0 mmol) and 4-formylimidazole (4.45 g, 46.3 mmol) were dissolved in 1 ,2-DCE (100 mL) and acetic acid (50 mL). Sodium triacetoxyborohydride (4.45 g, 21.0 mmol) was added all at once and the mixture was stirred at room temperature for 1h. Saturated NaHCθ3
(50 mL) was added followed by ammonium hydroxide (50 mL). The mixture was stirred for 2h, concentrated and the residue was partitioned between water (100 mL) and ethyl acetate (200mL). The organic layer was washed with water (100mL), brine (100 mL), dried (Na2SO4), concentrated and chromatographed (silica gel, 5.1 X 15 cm, 95% dichloromethane, 5% methanol) to yield the free base of Example 225 as a brown solid (4.9 g). This brown solid was further purified by preparative HPLC (YMC S-15 ODS column, 50 X 500 mm; solvent A, 0.1% TFA in 90% water, 10 % methanol; solvent B, 0.1% TFA in 10% water, 90% methanol: 20-100% B in 60 min, flow rate 25 mL/min). Fractions containing the desired product were combined, concentrated and lyophilized. This lyophilate was dissolved in acetonitrile (50 mL) and 1N HCl (50 mL). This mixture was concentrated and lyophilized. This procedure is repeated to provide Example 226 as a yellow solid (2.3 g, 35%) MS (M + H)+ 437 1 H-NMR (CD3OD, 400 MHz) d (ppm) 8.95 (1H, m), 7.68-7.30 (13H, m), 7.04
(1 H, m), 5.21-5.10 (1H, m), 4.78-4.63 (2H, m), 4.63-4.48 (1 H, m), 4.38 (1 H, m), 3.81-3.76 (1H, m), 3.28-3.15 (1H, m), 2.98-2.93 (1H, m), 2.88-2.80 (1H, m), 2.09 (2H, s), 1.62 (1 H, s).
Example 227
Figure imgf000180_0001
7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5-tetrahydro- 1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, trifluoroacetate (1 :2).
A. 7-Bromo-4-[ethenylsulfonyl]-2,3,4,5-tetrahydro-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine To a mixture of Compound B of Example 224 (250 mg, 0.79 mmol) in THF (20 mL) was added sequentially 2-chloroethane sulfonyl chloride (0.1 mL, 0.95 mmol) and DIEA (0.18 mL, 1.98 mmol). The solution was stirred under argon at room temperature for 18 hours, partitioned between aqueous hydrochloric acid (100 ml, 1 N), and ethyl acetate (100 mL), and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to provide a crude oil which was purified by flash chromatography (silica, hexane : ethyl acetate 3:1) to provide Compound A as a clear oil (85 mg, 26 %).
B. 7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5- tetrahydro-3-(phenylmethyl)-4H-1 ,4-benzodiazepine
To a solution of Compound A (85 mg, 0.21 mmol) in THF (5 mL) was added a solution of dimethylamine (2 mL, 2M in THF). The solution was heated in a sealed pressure bottle at 60°C for 48 hrs, cooled to room temperature and concentrated under vacuum to afford crude Compound B as an oil. C . 7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2, 3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, trifluoroacetate (1:2).
To a stirred solution of Compound B (90 mg, crude, assume 0.21 mmol), 4-formyl imidazole (30 mg, 0.32 mmol), dichloroethane (4 mL) and acetic acid (2 mL) at room temperature was added sodium triacetoxyborohydride (67 mg, 0.32 mmole). The solution was stirred for 48 hour, diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 ml, cone), and stirred for an additional 18 hours. The mixture was extracted with ethyl acetate (2 x 25 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (25 mL, saturated solution), and then ammonium chloride (25 mL, sat aqueous solution), dried (Na2S04), and concentrated in vacuo to a semi-solid. The crude was purified by preparative HPLC (aqueous methanol gradient containing 0.1% trifluoroacetic acid, C- 18 column) and lyophilized to provide Example 227 as a white solid (50 mg, 44 % yield from Compound A), mp 118-120 °C. Analysis calculated for C24H3θNδOSBr «1.0 H2O «2.0 TFA.
Calc'd: C, 43.20; H, 4.40; N, 9.00; S, 4.12; Br, 10.26. Found: C, 43.85; H, 4.00; N, 8.35; S, 4.39; Br, 9.43.
Example 228
Figure imgf000181_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4- [(1 ,2,3,4-tetrahydro-1 -quinolinyl)carbonyl]-1 H-1 ,4- benzodiazepine, monohydrochloride.
Example 228 was prepared from N-chlorocarbonyl-1 ,2,3,4- tetrahydroquinoline as described for Example 35, except that the acylation product was chromatographed (silica, 8:2 chloroforπv.ethyl acetate). MS (M + H)+ 464
Analysis calculated for C29H29N5O *1.0 H2O »1.1 HCl »0.25 ether.
Calc'd: C, 66.70; H, 6.46; N, 12.96; Cl, 7.22. Found: C, 66.88; H, 6.36; N, 12.62; Cl, 7.30.
Example 229
Figure imgf000182_0001
N-Ethyl-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,7- diphenyl-4H-1 ,4-benzodiazepine-4-carboxamide, monohydrochloride.
Example 229 was prepared from N-chlorocarbonyl-N-ethyl-aniline as described for Example 35. The HCl salt was prepared by dissolving the product in methanol, adding 4N HCl in dioxane, evaporation, redissolving in methanol and precipitating with ether. MS (M + H)+ 452 Analysis calculated for C-28H29N5O »0.4 H2O »1.2 HCl »0.25 ether.
Calc'd: C, 66.85; H, 6.48; N, 13.44; Cl, 8.16. Found: C, 66.78; H, 6.38; N, 13.49; Cl, 8.05.
Example 230
Figure imgf000183_0001
4-[(2,3-Dihydro-1 H-indol-1 -yl)carbonyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 230 was prepared from N-chlorocarbonyl-indoline as described for Example 229, mp 156-166°C. MS (M + H)+ 450 Analysis calculated for C28H27N5O »0.5 H2O »1.5 HCl.
Calc'd: C, 65.52; H, 5.79; N, 13.65; Cl, 10.36. Found: C, 65.40; H, 5.74; N, 13.47; Cl, 10. 49.
Example 231
Figure imgf000183_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4- benzodiazepine, trihydrochloride. A. 2,3,4,5-Tetrahydro-1 -(trif luoroacetyl)-4-(methylsulf onyl)-
3-(phenylmethyl)-7-bromo-1 H-1 ,4-benzodiazepine
Trifluoroacetic anhydride (1.2 mmol, 165 mL) was added to a solution of Compound A of Example 78 (0.3 mmol) and triethylamine (2.75 mmol, 384 mL) in CH2CI2 (4 mL) and the homogeneous solution was maintained at rt for 5 hrs. The reaction was concentrated and purified by flash chromatography (40%EtoAc/Hex) to isolate Compound A as a fluffy white solid (100 mg, 68%). MS (M+NH4) 508.
B. 2,3,4,5-Tetrahydro-1 -(trifluoroacetyl)-4-(methylsulfonyl)-
3-(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine
Compound A (0.15 mmol), 4-stannylpyridine (0.3 mmol, 110 mg) and 15 mol% Pd(PPh3)4 (26 mg) in 3 mL THF was degassed and heated to reflux under argon. Over the period of 48 hrs, an additional 20 mol% catalyst was added until starting material was fully consumed. The reaction was concentrated and purified by flash chromatography (EtOAc) to isolate Compound B as a yellow oil (46 mg, 63%). MS (M+H) 490.
C . 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4- benzodiazepine, trihydrochloride
NaOH (5 drops of 2N NaOH aqueous solution) was added to a solution of Compound B (40 mg, 0.082 mmol) in 3 mL MeOH and the mixture was maintained at RT for 20 min and concentrated. The residue was partitioned between 2N NaOH (5 mL) and 10% isopropanol-CH2CI2 (5 mL) and extracted with 10% isopropanol-CH2CI2 (3X5 mL), dried over Na2S04 and concentrated. This material was dissolved in 1 mL of 1 :1 AcOH:dichloroethane and treated with 4-formylimidazole (0.66 mmol, 63 mg) and NaBH(OAc)3 (0.66 mmol, 140 mg) and the mixture was heated at 50°C for 2 hrs and concentrated. The residue was partitioned between 2N NaOH- brine-sat. NH40H (10:10:0.3, 23 ml total) and 10% isopropanol-CH2CI2 (5 mL) and the aqueous phase was extracted with 10% isopropanol-CH2CI2 (2X5 mL). The combined organic phases were concentrated and purified with prep. HPLC (YMC S5 ODS 20 X100 mm, gradient elution with 15 to 75 % buffer B over 60 min. Buffer A = MeOH : H2θ:TFA (10:90:0.1); Buffer B = MeOH:H2θ:TFA (90:10:0.1); flow rate 25 ml/min). The TFA salt was converted to HCl salt with 1 N HCl to produce εxample 231 as a yellow solid (6.0 mg, 13%). MS (M+H)+ 474
1H NMR (CD30D) d 8.9 (s, 1H), 8.7 (m, 2H), 8.3 (m, 2H), 7.8 (m, 2H), 7.5 (s, 1 H), 7.3 (m, 4H), 7.0 (d, J=9Hz, 1 H), 4.8 (d, J=8Hz, 2H), 4.65 (t, J=14Hz, 2H), 4.45 (br s, 1 H), 3.7 (dd, J=7,14 Hz, 1 H), 3.4 (dd, J=7,5 Hz, 1 H), 2.96(dd, J=14,7 Hz, 1 H), 2.8 (dd, J=14,7 Hz, 1H), 2.3 (s, 3H).
Example 232
Figure imgf000185_0001
(R)-4-[[2-(Dimethylamino)ethyl]sulfonyl]-2,3,4,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate (1 :1).
A. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
Compound A was prepared from Compound A of Example 224 as described for Compound B of Example 75.
B. (R)-7-Phenyl-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-
1 ,4-benzodiazepine
To a mixture of Compound A (500 mg, 1.58 mmol) in toluene (20 mL) and aqueous sodium bicarbonate (10 mL, saturated solution) under argon was added a solution of phenyboronic acid (385 mg in 5 ml absolute ethanol). Tetrakis(triphenylphosphine) palladium(O) (91 mg) was added, and the solution heated to reflux (~80°C). After 18 hours, the mixture was cooled to room temperature and partitioned between aqueous sodium hydroxide (100 mL, 3N) and ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (2 x 200 mL), and the organic layers were combined, dried (MgS04) and concentrated in vacuum to an oil, which was purified using flash chromatography (60 g silica, 10:0.5: 0.05 ethyl acetate : methanol : ammonium hydroxide) to provide Compound B (350 mg, 70 %) as a waxy solid
C . (R)-4-Ethenylsulf onyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
To a mixture of Compound B (45 mg, 0.14 mmol) in methylene chloride (5 mL) and aqueous sodium hydroxide (1mL, 1M solution) was added 2-chloroethane sulfonyl chloride (0.8 mL, 0.07 mmol). Additional portions of 2-chloroethane sulfonyl chloride (0.1 mL, 0.2 mL, 0.2 mL) were added over a period of 6 hours and the mixture was stirred for 18 hours, poured into brine and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuum to an oil, which was purified using preparative HPLC (ODS column, aqueous methanol gradient containing trifluoroacetic acid). Appropriate product containing samples were pooled and concentrated under vacuum to provide Compound C (10 mg, 17 %) as a clear oil.
D . (R)-4-[[2-(Dimethylamino)ethyl]sulfonyl]-2, 3,4,5- tetrahydro-7-phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
To a solution of Compound C (20 mg, 0.025 mmol) in tetrahydrofuran (2 mL) was added a solution of dimethyl amine (1 mL, 2M in THF). The solution was heated in a sealed pressure bottle at 60°C for 18 hrs, cooled to room temperature and concentrated in vacuum to an oil.
E. (R)-4-[[2-(Dimethylamino)ethyl]sulfonyl]-2,3,4,5- tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-3- (phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :1 )
A solution of Compound D (20 mg, crude, assume 0.05 mmol) and 4-formyl imidazole (10 mg, 0.1 mmol) in dichloroethane (4 mL) and acetic acid (2 mL) was stirred at room temperature for 30 min. Sodium triacetoxy borohydride (22 mg, 0.1 mmole) was added and the solution was stirred for 48 hour, diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 ml, cone), and stirred for an additional 30 min. The mixture was extracted with ethyl acetate (2 x 25 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (25 ml, saturated solution), and then ammonium chloride (25 mL, sat aqueous solution), dried (Na2S04), and concentrated in vacuo to a semi-solid. The crude product was purified by preparative HPLC (aqueous methanol gradient containing 0.1% trifluoroacetic acid, C-18 column) and lyophilized to provide Example 232 as a white solid (10 mg, 37 % yield from Compound C). mp 115-120 °C. MS (M+H)+ 530 1 H NMR (200 MHz, CD3OD) d 8.8 (d, 1H), 7.7-7.4 (m, 12H), 7.1 (d, 1H), 4.9
(s, 6H), 3.4-3.1 (m, 8 H), 3.8-3.2 (m,8H), 2.7 (s, 6H).
Example 233
Figure imgf000187_0001
[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethy l)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, cyclohexyl ester, dihydrochloride.
A solution of cyclohexanol (0.14 mL, 0.137 g, 1.38 mmol) and phosgene (0.14 mL, 2 M solution in THF) was stirred at 4°C for 2 hrs. To this cold solution were added triethylamine (0.19 mL, 0.14 g, 1.38 mmol) and Example 26 (0.050 g, 0.12 mmol). After stirring for 16 hrs at 4°C the mixture was diluted with chloroform and NaHC03 solution and the layers were separated. The aqueous layer was extracted with CHCI3 (2x30 mL) and the combined organic layers were washed with brine (1x30 mL), dried over MgS04, filtered and concentrated. The residue was treated with MeOH and 1 N NaOH for 30 min. The crude product was purified by preparative HPLC (aqueous methanol gradient containing 0.1% trifluoroacetic acid, C-18 column) and lyophilized. The residue was treated with HCI/ether to afford Example 233 (0.030 g, 46 %) as a light yellow solid. MS (M + H)+ 524
1 H NMR ( 270 MHz, CD3OD): d 8.0-6.9 (m, 11 H), 6.81 (d, 0.5H, J = 8 Hz),
5.85 (d, 0.5H, J = 9 Hz) 5.85 (m, 1H), 4.4-4.0 (m, 3H), 3.9-3.7 (m, 0.5H), 3.4- 3.1 (m, 1.5H), 2.88 (m, 1H), 2.0-1.2 (m, 12 H).
Example 234
Figure imgf000188_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1-(1 -methyl-1 H-imidazol-5- yl)methyl)-4-(methylsu!fonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
A. (R)-7-Bromo-2,3,4,5-tetrahydro-1-[(((1 ,1-dimethylethoxy)- carbonyl)-1 H-imidazol-4-yl)methyl]-4-(methylsulfonyl)-3- (pheny lmethyl)-1 H-1 ,4-benzodiazepine
To a solution of 260 mg (0.55 mmol) of Example 224 in 10 ml of methylene chloride was added 131 mg (0.60 mmol) of BOC anhydride and 3 mg (0.025 mmol) of DMAP. The clear colorless solution was stirred at rt under argon for 3 hr. An additional 40 mg of BOC anhydride was added and stirring was continued overnight. The mixture, without workup, was placed a 30 cc column of silica gel and eluted with 25% ethyl acetate:hexane to afford 290 mg (0.55 mmol, 100%) of Compound A as a solid white foam.
B. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 -methyl-1 H-imidazol- 5-yl)methyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
To a solution of 275 mg (0.48 mmol) of Compound A and 0.091 ml (0.52 mmol) of DIEA in 5 ml of methylene chloride, at -78°C and under argon, was added dropwise 0.059 ml (0.52 mmol) of methyl trifiate. The mixture was allowed to warm to rt over 3 hr. An additional 0.091 ml (0.52 mmol) of DIEA and 0.059 ml (0.52 mmol) of methyl trifiate were added. Stirring was continued at rt overnight. Three more additions of 0.091 ml (0.52 mmol) of diisopropylethylamine and 0.059 ml (0.52 mmol) of methyl trifiate were made at 1 hr intervals. The reaction, without workup, was placed a 50 cc column of silica gel. Elution with CHCI3:MeOH (98:2) afforded 134 mg of the free base of Example 234 as a white foam. To this material, as a solution in 2 ml of ethyl acetate, was added dropwise 0.26 ml of 1 N HCI/ether. The resulting solid was filtered to give Example 234 (102 mg, 38%) as a white solid. MS (M + H)+ 489, 491
Analysis calculated for C22H24N4O2CI «0.25 EtOAc -1.25 HCl.
Calc'd: C, 49.59; H, 5.11 ; N, 10.06. Found: C, 49.97; H, 5.15; N, 9.90.
Example 235
Figure imgf000189_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1-[(1-methyl-1 H-imidazol-5-yl)methyl]- 4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
To a solution of 200 mg (0.38 mmol) of (R)-7-cyano-2,3,4,5- tetrahydro-1-[(((1 ,1-dimethylethoxy)-carbonyl)-1 H-imidazol-4-yl)methyl]-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (prepared from Example 224 as described for Compound A of Example 225) in 2 mL of methylene chloride, at -78°C and under argon, was added dropwise 59 μL (0.48 mmol) of methyl trifiate. The reaction was allowed to warm to rt, during which time a white precipitate was obtained. Stirring was continued at rt for 3 hr, after which time 140 μL (0.8 mmol) of DIEA was added and stirring continued overnight at rt. The mixture, without workup, was subjected to flash chromatography on a 30 cc column of silica gel. Elution with 2% MeOH-CHCI3 afforded 122 mg (0.28 mmol, 74%) of a clear colorless oil which crystallized on standing. This material was converted to its hydrochloride by the addition of 0.28 mL of 1 M HCl in ether to a methylene chloride solution (2 mL) of the free base. A white precipitate was obtained which on filtration afforded 90 mg of Example 235 as a white powder. MS (M+H)+ 436
Example 236
Figure imgf000190_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)- 7-phenyl-3-(phenylmethyl)-1 H-pyrido[3,2-e]-1 ,4-diazepine, monohydrochloride. BMS-214693
A. 2-Hydroxy-5-nitro-6-methylpyridine
To a suspension of a 2:1 mixture of 2-amino-5-nitro-6- methylpyridine and 2-amino-3-nitro-6-methyipyridine (2.5 g, 16.3 mmol) in 15 mL of water at 0°C was added concentrated sulfuric acid (5 mL), followed by a solution of NaN02 (2.25 g, 32.6 mmol) in 5 mL of water dropwise over 90 minutes. The solution was stirred 5 hours as it warmed to room temperature, cooled to 0°C and filtered. The solid was washed with water (2x) and dried under vacuum to afford 1.84 g of a >4:1 mixture (by HPLC) of Compound A and 2-hydroxy-3-nitro-6-methylpyridine (73%) as a tan solid. B. 2-Chloro-5-nitro-6-methylpyridine
A mixture of Compound A, 2-hydroxy-3-nitro-6-methylpyridine (0.93 g, 6.05 mmol) and phosphorus pentachloride (48.9 g, 235 mmol) in toluene (10 mL) was heated at 92°C for 16 hours and cooled to 0°C. Ice was added and the mixture was stirred and partitioned. The aqueous layer was washed with toluene and the combined organic phases were dried (magnesium sulfate), filtered and evaporated to afford 1.03 g of a 6:1 mixture of Compound B and 2-chloro-3-nitro-6-methylpyridine (100%) as a reddish brown crystalline semi-solid.
C . 2-Phenyl-5-nitro-6-methylpyridine
A mixture of Compound B and 2-chloro-3-nitro-6-methylpyridine (0.42 g, 2.40 mmol) in THF (10 mL) was degassed wtih nitrogen. Tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol) was added and the mixture was stirred 30 minutes. Phenylboronic acid (0.44g, 3.6 mmol) and 2M Na2C03 (1.8 mL) were added and the mixture was heated at 75°C for 17 hours and stirred at room temperature for 48 hours. Methylene chloride was added and the mixture was filtered through celite and partitioned. The mixture was washed with saturated aqueous NaHC03, dried (magnesium sulfate), filtered and evaporated to afford 0.77 g of brown solid. Flash chromatography (silica, 10% ethyl acetate/hexanes) afforded 0.37 g of Compound C (72%) as an off white solid and 0.05 g of 2-phenyl-3- nitro-6-methylpyridine (10%) as an oil.
D . 2-Phenyl-5-amino-6-methylpyridine
To a suspension of Compound C (3.0 g, 14 mmol) in concentrated HCl (30 mL) was added tin chloride dihydrate (9.91 g, 44 mmol) in portions over 45 minutes. The solution was allowed to warm to room temperature over 2 hours, heated at 78°C for 15 minutes, cooled to 0°C, neutralized with 4M NaOH and extracted with methylene chloride (3x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated to afford 2.62 g of Compound D (100%) as a yellow oil which crystallized on standing.
E. 2-Phenyl-5-(phenylsulfonylamino)-6-methylpyridine
A mixture of 2-phenyl-5-amino-6-methylpyridine (2.29 g, 12.4 mmol) and benzenesulfonyl chloride (1.65 mL, 12.9 mmol) was heated at 88°C for 15 hours. The mixture was cooled and the resulting glass was dissolved in methylene chloride/10% NaOH. The mixture was partitioned, the organic phase was washed with 10% NaOH and the combined aqueous phases were acidified with concentrated HCl and extracted with methylene chloride (2x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated to afford 3.40 g of Compound D (85%) as a light yellow crystalline solid.
F. 2-Phenyl-5-(phenylsulfonylamino)-6-methylpyridine-N- oxide
To a suspension of Compound E (3.0 g, 9.24 mmol) in acetic acid (28 mL) was added 30% aqueous hydrogen peroxide (9.25 mL). The mixture was heated at 72°C for 4 hours and at 62°C for 22 hours. An additional 3 mL of H202 was added and the mixture was heated at 54°C for 20 hours and poured onto ice. The mixture was allowed to stand overnight, 200 mL of water was added and the resulting solid was filtered, washed with water and ether and dried under vacuum to afford 1.43 g (46%) of Compound F as a yellow solid contaminated with Compound E. The combined water and ether washes were extracted with methylene chloride to afford 1.0 g of an approximate 4:1 mixture of Compound E and Compound F. MS (M+H)+ 341.1.
G. 2-Phenyl-5-(phenylsulfonylamino)-6-acetoxymethyl- pyridine A solution of crude Compound F (0.50 g, <1.47 mmol) and acetic anhydride (2.5 mL) in acetic acid (5 mL) was heated at 90°C for 4 hours, cooled, and poured onto ice. After standing overnight, the mixture was extracted twice with methylene chloride and the combined organic extracts were dried (MgS04), filtered and evaporated to afford Compound G (0.60 g, >100%) as a yellow foamy gum.
H . 2-Phenyl-5-(phenylsulfonylamino)-6-hydroxymethyl- pyridine
A mixture of Compound G (0.60 g, <1.47 mmol) in 2M NaOH (2 mL) was heated at 50°C for 2.25 hours and cooled to 0°C. Methylene chloride was added, followed by concentrated aqueous HCl until the solid dissolved. Solid Na2HP04 was added until the aqueous phase was pH 7, and the mixture was partitioned. The aqueous phase was extracted with methylene chloride and the combined organic extracts were dried (MgS04), filtered and evaporated. The residue was flash chromatographed on silica with 50% ethyl acetate/hexanes to afford 0.09 g of Compound F and 0.24 g of Compound H (48% from crude compound F) as a gum.
I. 2-Phenyl-5-(phenylsulfonylamino)-pyridine-6- carboxaldehyde
To a solution of crude Compound H (0.70 g, 2.06 mmol) in THF (10 mL) was added MnO2 (0.36 g, 4.11 mmol). The mixture was stirred at room temperature and additional MnO2 was added at the following times: 1 hour, 0.36 g; 2 hour, 0.36 g; 3 hour, 0.36 g; 7.5 hour, 0.72 g; 22.5 hour, 0.72 g; 32 hour, 0.72 g. After stirring for 32.5 hours, the mixture was filtered through celite, the pad was washed three times with celite and the filtrate was evaporated to afford 0.55 g of Compound I (79%) as an orange solid. MS (M+H)+ 339.0.
J. D-[N-(2-phenyl-5-(phenylsulfonylamino)-6- pyridinylmethyl)-phenylalanine], methyl ester A suspension of Compound I (0.55 g, 1.62 mmol), D-phenylalanine methyl ester hydrocloride (1.05 g, 4.88 mmol), NaOAc (0.40 g, 4.88 mmol) and 10% Pd/C (50 mg) in 4 L methanol/2 mL acetic acid was hydrogenated wfth a balloon for 18 hours and filtered through celite. The pad was rinsed twice with methanol and the filtrate was evaporated. The residue was partitioned between pH 7 phosphate buffer and methylene chloride. The aqueous phase was extracted with methylene chloride and the combined organic extracts were dried (MgS04), filtered and evaporated to afford Compound J (1.21 g, >100%).
K. (R)-2,3,4,5-Tetrahydro-7-phenyl-3-(phenylmethyl)-1 H- pyrido[3,2-e]-1 ,4-diazepin-2-one
A mixture of Compound J (1.21 g, < 1.62 mmol) and polyphosphoric acid (16 g) was heated at 100°C for 5 hours. Ice and methylene chloride were added and the mixture was chilled, made basic with 4N NaOH and partitioned. The aqueous phase was washed twice with methylene chloride and the combined organic extracts were dried (MgS04), filtered and evaporated. The residue was flash chromatographed on silica with 75% ethyl acetate/hexanes to afford 0.31 g (58% from Compound I) of Compound K as an off white solid. MS (M+H)+ 330.0.
L. (R)-2,3,4,5-Tetrahydro-4-(methylsulfonyl)-7-phenyl-3- (phenylmethyl)-l H-pyrido[3,2-e]-1 ,4-diazepin-2-one
To a solution of Compound K (117 mg, 0.36 mmol) and TEA (0.06 mL, 0.43 mmol) in methylene chloride (3 mL) at 0°C was added mesyl chloride (0.033 mL, 0.43 mmol). The solution was stirred at 0°C for 30 minutes and at room temperature for 90 minutes. Additional TEA (0.06 mL) and mesyl chloride (0.032 mL) were added and the solution was stirred for 1 hour and partitioned between aqueous NaHC03 and methylene chloride containing a little isopropanol (<10%). The aqueous layer was washed with methylene chloride and the combined organic extracts were dried (MgSO4), filtered and evaporated to afford 145 mg of Compound L as a solid (100%). MS (M+H)+ 408.1.
M. (R)-2,3,4,5-Tetrahydro-4-(methylsulfonyl)-7-phenyl-3-
(phenylmethyl)-l H-pyrido[3,2-e]-1 ,4-diazepine
To a solution of Compound L (53 mg, 0.13 mmol) in THF (2 mL) at 0°C was added 1 M borane in THF (0.39 mL). The solution was allowed to warm to room temperature overnight, methanol was added and the mixture was evaporated. The residue was dissolved in a small amount of 10% HCl and methanol, warmed until a clear solution was obtained, and the methanol was evaporated. Methylene chloride was added followed by solid K2CO3 until the aqueous layer was pH 11. The mixture was partitioned and the aqueous layer was washed with methylene chloride and the combined organic extracts were dried (MgS04), filtered and evaporated. The residue was subjected to preparative TLC on silica with 50% ethyl acetate/hexanes. The main mid Rf band was cut and extracted with methylene chloride containing a few drops of methanol to afford 25 mg of Compound M as a light yellow foam (49%).
N . (R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-7-phenyl-3-(phenylmethyl)-1 H-pyrido[3,2-e]-1 ,4- diazepine, monohydrochloride.
To a solution of Compound M (24 mg, 0.06 mmol) and imidazole-4- carboxaldehyde (17 mg, 0.18 mmol) in dichloroethane (1 mL)/ acetic acid (0.5 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol). The solution was stirred 1 hour and additional aldehyde (16 mg) and hydride (16 mg) were added The solution was stirred 45 minutes and additional hydride (16 mg) was added. NH4OH (0.5 mL) was added, followed by ethyl acetate and aqueous NaHC03. The mixture was partitioned and the aqueous layer was washed with ethyl acetate and the combined organic extracts were washed with saturated NaHCO3 and brine, dried (MgS04), filtered and evaporated to afford the free base of Compound N (25 mg, 89%) as a white foamy gum. This material was dissolved in methylene chloride and the solution filtered through glass wool and evaporated. The residue was dissolved in methanol, 0.5 mL of 1 M HCl in ether was added and the mixture was evaporated. The residue was evaporated from methanol, dissolved in 2 mL of methanol and the solution filtered through glass wool. The filtrate was evaporated and the residue dissolved in 0.5 mL of methanol. Ether (10 mL) was added and the resulting precipitate was filtered, rinsed with ether and dried to afford Example 236 (24 mg) as a yellow solid. MS (M+H)+ 474.3. 1 H (CD3OD) d 2.18, 3H, s; 2.76-2.92, 2H, m; 3.65, 1 H, dd (J = 4.7, 15.2 Hz);
3.98, 1 H, dd (J = 10.6, 15.2 Hz); 4.75, 1 H, m; 5.18, 1 H, d (J = 18.8 Hz); 7.26- 7.40, 5H, m; 7.58-7.61 , 4H, m; 7.76-7.904H, m.
Example 237
Figure imgf000195_0001
4-[2-(4-Chlorophenyl)-1 ,2-dioxoethyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride. A solution of HOAt (0.013 gm, 0.092 mmol) in DMF (0.5 mL) was added to 2-(4-chlorophenyl)-2-oxo-acetic acid ( 0.017 g, 0.092 mmol). Solutions in DMF of Compound B of Example 33 (0.2 M, 0.46 mL, 0.092 mmol) and DIC (0.2 M, 0.014 mL, 0.092 mmol) were added to the mixture, which was stirred at room temperature for 16h. The mixture was purified by ion exchange chromatography on a solid phase extraction cartridge using the following protocol:
1) Conditioned a Varian solid phase extraction column (1.5 g, SCX cation exchange) with 10 mL of MeOH/CH2Cl2 2) Loaded mixture onto column using a 10 mL syringe to pressurize the system
3) Wash column with 3 X 7.5 mL MeOH/CH2Cl2 (1 :1)
4) Wash the column with 1 X 7.5 mL of 0.01 N ammonia in MeOH
5) Eluted column with 7.5 mL of 1.0 N ammonia in MeOH and collect into a tared receiving tube.
The product was concentrated on a Savant Speed Vac (approx. 2mm Hg for 20 hr). The residue was dissolved in CH3CN (2 mL), 1N HCl (0.10 mL) and water (1 mL) and lyophilized to afford Example 237 (0.042 gm, 86%) as a white lyophilate. MS: (M+H)+ 471
Analysis calculated for C27H23N4O2CI -0.15 CH3CN -1.0 HCl -0.84 H2O.
Calc'd: C, 61.40; H, 4.93; N, 10.88. Found: C, 61.41 ; H, 5.02; N, 11.28.
Example 238
Figure imgf000197_0001
4-(1 ,2-Dioxopropyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 238 was prepared from pyruvic acid as described for Example 237. MS: (M+H)+ 375
Analysis calculated for C22H22 4O2 *1.0 HCl »0.67 H2O.
Calc'd: C, 62.47; H, 5.80; N, 13.25. Found: C, 62.46; H, 5.59; N, 13.28.
Example 239
Figure imgf000198_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-(4- nitrophenyl)-1 ,2-dioxoethyl]-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 239 was prepared from 4-nitrophenylpyruvic acid as described for Example 237. MS: (M+H)+ 482
Analysis calculated for C27H23N5O4 *1.0 HCl «0.38 H2O.
Calc'd: C, 61.79; H, 4.76; N, 13.34. Found: C, 61.80; H, 4.72; N, 13.54.
Example 240
Figure imgf000198_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-(4- methoxyphenyl)-1 ,2-dioxoethyl]-7-phenyl-1 H-1 ,4- benzodiazepine, hydrochloride. Example 240 was prepared from 4-methoxyphenylpyruvic acid as described for Example 237. MS: (M+H)+ 467 Analysis calculated for C28H26N4O3 «1.0 HCl «0.79 H2O.
Calc'd: C, 65.02; H, 5.57; N, 10.83. Found: C, 65.01 ; H, 5.66; N, 10.75.
Example 241
Figure imgf000199_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(3,3,3- trifluoro-1 ,2-dioxopropyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2).
Example 241 was prepared from trifluoropyruvic acid as described for Example 237, with methylene chloride as cosolvent. Purification was by reverse phase preparative HPLC (aqueous methanol, 0.1% TFA). MS: (M+H)+ 429 Analysis calculated for C22HigN4θ2F3 »1.5 TFA »0.81 H2O.
Calc'd: C, 48.90; H, 3.63; N, 9.12. Found: C, 48.90; H, 3.58; N, 9.13. Example 242
Figure imgf000200_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -[(1 H-imidazol-4-yl)-methyl]-4- (methylsulf onyl)-3-(phenylmethyl)-1 H-pyrido[3,2-e]-1 ,4- diazepine, hydrochloride.
A. 2-Chloro-5-(phenylsulfonylamino)-6-methylpyridine
Compound A was prepared from Compound B of Example 236 as described for Compound D of Example 236 and Compound E of Example 236.
B. 2-Chloro-5-(phenylsulfonylamino)-6-methylpyridine-N- oxide
To a suspension of Compound A (3.0 g, 10.6 mmol) inTFA (12.5 mL) was added 30% aqueous hydrogen peroxide (2.2 mL). The mixture was heated at reflux for 80 minutes. An additional 2.5 mL of H202 was added and the mixture was heated at reflux for 95 minutes. An additional 2.5 mL of H202 was added and the mixture was heated at reflux for 1 hour and poured onto ice. The mixture was allowed to stand overnight and was filtered. The solid was washed with water and dissolved in 10% isopropanol/methylene chloride and the solution dried to afford 2.44 g of Compound B contaminated with Compound A. An additional 0.33 g of impure compound B later precipitated from the aqueous filtrate for a combined yield of 2.77 g (88%). (M+H)+ 298.9.
C . 2-Chloro-5-(phenylsulfonylamino)-6-hydroxymethyl- pyridine
Compound C was prepared as a gum from Compound B as described for Compounds G and H of Example 236. (M+H)+ 299.0. D . 2-Chloro-5-(phenylsulfonylamino)-pyridine-6- carboxaldehyde
To a solution of crude Compound C (2.45 g, 8.20 mmol) in THF (20 mL) was added MnO2 (1.43 g, 16.4 mmol). The mixture was stirred at room temperature and additional MnO2 was added at the following times: 1 hour, 2.86 g; 28 hour, 2.86 g. After stirring for 21 hours, the mixture was directly flash chromatographed (25% ethyl acetate/hexanes) to afford 0.82 g of crude compound D.
E . D-[N-(2-chloro-5-(phenylsulfonylamino)-6- pyridinylmethyl)-phenylalanine], methyl ester
To a solution of crude Compound D (0.81 g, 2.73 mmol), D- phenylalanine methyl ester hydrochloride (0.88 g, 4.10 mmol) and NaOAc (0.67 g, 8.20 mmol) in 15 mL methylene chloride/3 mL acetic acid was added sodium triacetoxyborohydride (0.87 g, 4.10 mmol) in aliquots over 90 minutes. The mixture was stirred for 90 minutes and partitioned between pH 7 phosphate buffer and methylene chloride. The aqueous phase was extracted with methylene chloride and the combined organic extracts were dried (MgSO4), filtered and evaporated to afford Compound E (1.62 g, >100%) as an orange gum.
F. (R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-7-chloro-3-(phenylmethyl)-1 H-pyrido[3,2-e]-1 ,4- diazepine, monohydrochloride Example 242 was prepared from Compound E as described in the following sequence: Compound K of Example 236, Compound L of Example 236, Compound M of Example 236, Compound N of Example 236. The HCl salt was precipitated from isopropanol with ether to afford Example 242 as a very hygroscopic foam. MS (M+H)+ 432.1.
13C (CDCI3, free base) d 37.96, 39.60, 47.97, 48.34, 55.73, 59.27, 118.66, 122.59, 124.89, 126.91 , 128.64, 129.16, 135.59, 137.15, 138.88, 139.63, 144.10, 144.54, 182.64 ppm. Example 243
Figure imgf000202_0001
6,7,8,9-Tetrahydro-5-(1 H-imidazol-4-ylmethyl)-8-(1 - naphthalenylcarbonyl)-2-phenyl-5H-pyrimido-[5,4- e][1 ,4]diazepine, monohydrochloride.
A. 2-Phenyl-5-bromo-4-pyrimidine carboxyiic acid
To a solution of mucobromic acid (16 g, 62 mmol) in 800 ml of water was added benzamidine hydrochloride hydrate (26 g, 166 mmol) and Triton B (100 ml, 40% in water). The solution was stirred 23 hours, filtered of a small amount of dark solid, and acidified with concentrated HCl. The gummy precipitate was filtered and recrystallized from 4:1 ethanol:water to afford 5.87 g (34%) of Compound A as a brown crystalline solid. Concentration of the mother liquor afforded an additional 1.72 g (44% total yield).
B. 2-Phenyl-5-(2-aminoethylamino)-4-pyrimidine carboxyiic acid A mixture of 3.0 g (10.8 mmol) of Compound A and 300 mg of copper sulfate in 15 ml each of water and ethylenediamine was heated at 100°C for 3 hr. The dark solution was evaporated to dryness and the semi- solid residue diluted with water to yield a voluminous white precipitate which was filtered, washed well with water, and air dried overnight to afford 2.45 g of Compound B as a light tan solid. The filtrate was evaporated to dryness and the residue diluted with water. Standing at rt afforded an additional 0.6 g of Compound B. The materials were combined and dried overnight at 60°C under vacuum to give 2.85 g (approx 100%) of Compound B as a pale yellow solid. C . 6,7,8,9-Tetrahydro-2-phenyl-5H-pyrimido-[5,4-e][1 ,4]- diazepin-9-one
To a suspension of 2.8 g (10.8 mmol) of Compound B in 100 ml of pyridine was added 3.1 g (16.3 mmol) of EDC and 2.2 g (16.3 mmol) of HOBT and the slurry was stirred at rt, under argon, for 36 hr. The resulting hazy solution was evaporated to dryness and the semi-solid residue diluted with 10% i-propanol:water and washed with brine (2x). A bright yellow precipitate formed in the aqueous layer during the washing. Filtration of this material afforded 1.9 g of crude Compound C. This material was suspended into methanol and heated on the steam bath. The remaining insolubles were removed by filtration and the filter cake again extracted with hot methanol. The combined filtrates were evaporated to dryness to afford 1.53 g (59 %) of Compound C as a pale yellow powder.
D . 6,7,8,9-Tetrahydro-2-phenyl-5H-pyrimido-[5,4-e][1 ,4]- diazepine
To a stirred solution of 100 mg (0.42 mmol) of Compound C in 2 ml of glyme was added 85 mg (2.1 mmol) of lithium aluminum hydride and the reaction heated at reflux for 18 hr. To the reaction was added 0.5 ml of pyridine and an additional 80 mg of LAH and heating continued at 85°C for an additional 18 hr. The mixture was quenched by the addition of 5 ml of ethyl acetate, followed by 0.5 ml of cone NH4OH. The resulting suspension was filtered and the filter cake washed well with ethyl acetate. The filtrate was evaporated to dryness and the resulting crude product used in the subsequent reaction without further purification. This material may also be flash chromatographed on silica with 10% methano ethyl acetate to afford pure Compound D as an orange crystalline solid.
E. 6,7,8,9-Tetrahydro-8-(1 -naphthaienylcarbonyl)-2-phenyl-
5H-pyrimido-[5,4-e][1 ,4]diazepine
To a solution of 80 mg (assumed 0.35 mmol) of crude Compound D in 3 ml of methylene chloride and 3 ml of 1 N sodium hydroxide was added 60 μl (0.4 mmol) of 1-naphthoyl chloride. The reaction was stirred at 0°C for 1 hr. The organic layer was separated, washed with sat. ammonium chloride, dried (MgSO4) and evaporated. The residue was subjected to flash chromatography on silica gel. Elution with ethyl acetate-hexane (3:1) afforded 40 mg (25 % from Compound C) of Compound E as a foam.
F. 6,7,8,9-Tetrahydro-5-(1 H-imidazol-4-ylmethyl)-8-(1 - naphthaienylcarbonyl)-2-phenyl-5H-pyrimido-[5,4- e][1 ,4]diazepine, monohydrochloride
To a solution of 23 mg (0.062 mmol) of Compound E in 1 ml of methylene chloride and 0.2 ml of acetic acid was added 10 mg (1 mmol) of 4-formyl imidazole. The reaction was allowed to stir for 15 min and 21 mg (1 mmol) of sodium triacetoxyborohydride was added. Additional 10 mg portions of the imidazole and 21 mg portions of the hydride were added as above after 1 ,2,3 and 4 hr of stirring. Stirring was continued overnight. The reaction was diluted with methanol and, without further workup, subjected to preparative HPLC on a YMC ODS-A S10 column with gradient elution from 0-100% solvent B (A: 10% MeOH-H2O + 0.1% TFA, B: 10% H20-MeOH + 0.1 % TFA). The appropriate fractions were combined and evaporated. The residue was converted to the hydrochloride salt by dilution with methanolic HCl and removal of solvent to give 31 mg of yellow solid. This material was dissolved into minimal methanol and precipitated by the dropwise addition of ether to afford 12 mg (39%) of pure Example 243 as a yellow powder. MS (M+H)+ 461.
1H NMR (CD3OD): d 3.69 (2H, bs), 3.90 (2H, m), 4.20 (1 H, m), 4.45 (1 H, m), 4.70 (1 H, m), 4.82 (1 H, m), 5.49 (1H, m), 7.32-8.30 (11 H, m), 8.43 (1 H, s), 8.60 (1 H, s), 8.95 (1H, m), 9.11 (1 H, s).
Example 244
Figure imgf000205_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylacetyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-7-Bromo-2,3,4,5-tetrahydro-4-(1 ,1 - dimethylethoxycarbonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a solution of 250 mg (0.79 mmol) of Compound B of Example 224 in 5 ml of methylene chloride, at rt and under argon, was added 192 mg (0.88 mmol) of BOC anhydride as a solution in 1 ml of methylene chloride. After 1 hr, an additional 100 mg of BOC anhydride was added and stirring continued an additional 0.5 hr. The reaction, without workup, was subjected to flash chromatography on a 50 cc column of silica gel. Elution with 20% EtOAc-hexane afforded 319 mg (96 %) of Compound A as a white solid.
B. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 -triphenylmethyl- imidazol-4-ylacetyl)-4-(1 ,1 -dimethylethoxycarbonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine
To a suspension of 2.2 g (6 mmol) of 1 -triphenylmethyl-4- imidazolyl-acetic acid in 50 ml of THF, at rt and under argon, was added 836 μl (6 mmol) of triethylamine. The resulting cloudy solution was cooled to - 30°C and 839 μl (6.6 mmoles) of -butylchloroformate was added dropwise. After stirring an additional 0.5 hr at -30°C, a solution of 500 mg (1.2 mmoles) of Compound A in 10 ml of THF was added dropwise. The reaction was allowed to warm to rt over three hours and stirring was continued overnight. The resulting black reaction was diluted with ethyl acetate and washed with brine (2x), dried (MgS04) and the solvent removed to yield a black foam residue which was subjected to flash chromatography on silica gel. Elution with 25% ethyl acetate-hexane afforded 376 mg (40 %) of Compound B as a gray solid foam, as well as 294 mg of Compound A.
C . (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 -triphenylmethy I- imidazol-4-ylacetyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride
A solution of 370 mg (0.48 mmol) of Compound B in 2 ml of 1 M HCl in acetic acid was stirred at rt for 0.5 hr. The reaction was evaporated to dryness at low temperature and the residue diluted with ethyl acetate. Filtration of the resulting solid afforded 280 mg (83%) of Compound C.
D . (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 -triphenylmethyl- imidazol-4-ylacetyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a solution of 280 mg (0.4 mmol) of Compound C in 3 ml of methylene chloride, at rt and under argon, was added 167 μl (1.2 mmoles) of triethylamine, followed by 46 μl (0.6 mmole) of methanesulfonyl chloride. After stirring 0.5 hr, an additional 167 μl of triethylamine and 46 μl methanesulfonyl chloride was added and stirring continued for an additional 0.5 hr. The solution, without workup, was subjected to flash chromatography on a 50 cc column of silica gel. Elution with 50 % ethyl acetate-hexane afforded 165 mg (55%) of Compound D as a solid white foam.
E. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylacetyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, monohydrochloride
To a solution of 80 mg (0.11 mmol) of Compound D in 2 ml of methylene chloride was added 0.5 ml of triethylsilane and 1 ml of TFA and the solution stirred at rt, under argon, for 3 hr. The reaction was evaporated to dryness to yield a white solid residue which was diluted with ether and stirred 0.5 hr. The solvent was decanted and the remaining insolubles washed twice more with ether. The remaining solid was taken into ethyl acetate and washed with sat NaHC03, brine, dried (MgSO and the solvent removed at give 45 mg of solid white foam. This material was dissolved in minimal methylene chloride and 90 μl of 1 M HCl in ether was added dropwise. The reaction was diluted with additional ether and the resulting slurry allowed to stand overnight under refrigeration. The solid was filtered under an atmosphere of nitrogen to afford 36 mg (62 %) of Example 244 as a white powder. MS (M+H)+ 503.
Analysis calculated for C22H23N4O3S »1.5 HCl.
Calc'd: C, 47.35; H, 4.42; N, 10.04. Found: C, 47.55; H, 4.41 ; N, 9.92.
Example 245
Figure imgf000207_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(2-1 H-imidazol-4-ylethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
To a solution of 80 mg (0.107 mmole) of the free base of Example 244 in 0.5 ml of THF, at rt and under argon, was added 1 ml of 1M borane in THF. The clear colorless solution was heated at reflux for 2 hr, 0.5 ml of cone. HCl was added and heating continued for an additional 2 hr at 65°C. The reaction was diluted with water and washed twice with ethyl acetate. The combined organic layers were backwashed once with brine, dried and the solvent removed to afford a clear oil residue which was subjected to flash chromatography on a 30 cc column of silica gel. Elution with CHCI3:MeOH:NH4OH (95:5:0.5) afforded 112 mg of an oil. This material was diluted with 0.5 ml cone. HCl and again heated at 80°C for 2 hr. After cooling to rt, the reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried (MgSO , and the solvent removed to give 30 mg of residue. Trituration of this material with ether afforded a white solid which was dissolved in 0.2 ml of methanol and precipitated by the dropwise addition of ether. Filtration of the resulting solid afforded 12 mg (21 %) of Example 245 as a white powder.
MS (M+H)+ (high res): calc, 489.0957. Obs, 489.096.
13C NMR (67.8 MHz, CD3OD): 24.7, 39.2, 40.3, 47.3, 53.3, 58.1 , 60.8, 113.3,
118.1 , 118.8, 128.3, 130.1 , 130.8, 131.0, 132.4, 134.0, 135.3, 139.8, 149.9 ppm.
Example 246
Figure imgf000208_0001
8-[(Cyclohexylcarbonyl)amino]-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, methyl ester, dihydrochloride.
A. 8-Amino-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine-4-carboxylic acid,1 ,1 - dimethylethyl ester
Compound A was prepared as a white solid from Compound D of Example 98 as described for Example 26. The crude free base was carried on. MS (M+H)+ = 434.
B. 8-(Cyclohexylcarbonylamino)-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine- 4-carboxylic acid, 1 ,1 -dimethylethyl ester
Compound B was prepared as a white foamy solid from Compound A as described for Example 27. The crude free base was carried on. MS (M+H)+ = 544. C . N-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepin-8-yi]cyciohexanamide
Compound C was prepared as a light brown solid from Compound B by treatment with HCI/dioxane in methanol at rt. MS (M+H)+ = 444.
D . 8-[(Cyclohexylcarbonyl)amino]-1 ,2,3,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine- 4-carboxylic acid, methyl ester, dihydrochloride
Methyl chloroformate (0.05 g, 0.09 mmol) was added to a stirred solution of Compound C (0.05 g, 0.09 mmol) in CH2CI2 at rt, under argon. After stirring for 3 days the mixture was partitioned with CHCI3 (5 mL) and NaHC03 (2 mL). The aqueous layer was extracted with CHCI3 (2 x 10 mL). The combined organic layers were washed with NaHCOg and brine, dried over MgS04, filtered and concentrated. The residue was purified by preparative HPLC, with a gradient of 50-100% aqueous methanol containing 0.1% TFA and the HCl salt was formed by treatment with 1M HCI/ether. MS (M+H)+= 502.
1H NMR (CDgOD): δ 8.8 (s, 1H), 7.45-7.1 (m, 7.5 H), 7.05 (m, 1H), 6.8 (m, 0.5
H), 4.67-4.35 (m, 4H), 4.58 (s, 3H), 3.4-3.0 (m, 3 H), 2.9 (m, 1 H), 2.7 (m, 1 H), 2.3 (m, 1H), 1.9-1.2 (m, 10 H).
Example 247
Figure imgf000209_0001
N-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1 naphthaienylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-1 - piperidinecarboxamide, dihydrochloride. Carbonyldiimidazole (0.045 g, 0.137 mmol), was added to a solution of Example 26 (0.050 g, 0.125 mmol), and triethylamine (0.038 mL, 0.275 mmol) in dry methylene chloride (1 mL) at rt under argon. After stirring for 2 hr, piperidine (0.013 mL, 0.13 mmol) was added. After stirring for 15 hr, the reaction was diluted with NaHCO3 and CHCI3. The organic layer was washed with NaHC03, water, and brine (1x3 mL each), dried over MgSO4, filtered and concentrated. The product was purified by reverse phase HPLC with a gradient of 40-90% aquous methanol with 0.1 % TFA and the HCl salt was formed by treatment with 1 M HCI/ether to afford Example 247 (0.006 g, 10 %). MS (M+H)+ 509.
1 H NMR (CD3OD): δ 8.5 (d, 1 H, J = 19 Hz), 8.06-7.9 (m, 2H), 7.69-7.3 (m, 7H), 7.2 (d, 0.5H, J = 7 Hz), 6.9 (d, 0.5H, J = 7 Hz), 6.5 (d, 0.5 H, J = 7 Hz), 5.89 (t, 0.5 H), 4.6-3.88 (m, 4.5 H), 3.6-3.3 (m, 6H), 3.18-2.85 (m, 1 ,5H), 1.65 - 1.55 (m, 6H).
Example 249
Figure imgf000210_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, ethyl ester, hydrochloride. A. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-2,5-dione
To a stirred solution of 5-bromoisatoic anhydride (150g, 563 mmol) in anhydrous pyridine (1.5L) under argon was added D-phenylalanine methyl ester hydrochloride (127 g, 590 mmol) and 4-dimethylaminopyridine (2g). The resulting solution was refluxed for 3 days and cooled to room temperature. The solvent was evaporated. The residue was dissolved in CH2CI2 (3 liter) and the solution was washed with 10% HCl and brine, dried over anhydrous Na2S04 and evaporated to give a foam which was suspended in Et20 (1.0L). The mixture was stirred and CH2CI2 (100 ml) was added to help break up the emulsion. After cooling 3 hr in an ice bath, the solid was filtered, washed with Et20 and a small amount of CH2CI2 and dried in high vacuum to give 152g (78.4%) of Compound A. 13C-NMR (DMSO-dβ) 33.31 , 53.69, 115.94, 123.31 , 126.43, 128.22, 129.39, 132.63, 134.97, 136.19, 137.76, 166.45, 171.11 ppm
B. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a stirred and chilled (0°, ice bath) solution of Compound A (100 g, 290 mmol) in anhydrous THF (1.5L) under argon was added borane tetrahydrofuran complex (1.0M solution, 1450 ml, 1450 mmol). The resulting solution was gently refluxed overnight. The solution was cooled to 0° and MeOH was slowly added until foaming ceased. The solvent was evaporated to dryness. The residue was diluted with MeOH (900 ml), an aqueous solution of 25% HCl (180 ml) added and the mixture was gently refluxed under argon for 2 hr. The resulting solution was cooled to 0° in an ice bath, Et20 (300ml) was slowly added and the mixture was stirred for 1 hr. The solid was filtered. The filtrate was evaporated and the residue and the solid were combined, rinsed with Et20 (500 ml) and acetone (500 ml) and suspended in CH2CI2 (2L) and water (1L). The pH of the slurry was adjusted to 11 with 3N NaOH. The CH2CI2 layer was separated. The aqueous layer was saturated with NaCl and extracted with CH2CI2. The combined CH2CI2 extracts were washed with brine, dried over anhydrous Na2S04 and evaporated to give 89 g (97% yield) of Compound B as light tan solid. 13C-NMR (CDCI3) 40.55, 52.19, 54.22, 61.74, 112.52, 120.25, 126.50, 128.60, 129.30, 130.13, 132.09, 133.96, 138.52, 148.13 ppm
C . (R)-2,3,4,5-Tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-7-carbonitrile
To a stirred suspension of Compound B (60 g, 190 mmol) in anhydrous 1-methyl-2-pyrrolidinone (600 ml) under nitrogen was added copper(l) cyanide (51 g, 569 mmol). The mixture was heated to 200° for 3.5hr. The mixture was slowly added to 15% ethylenediamine solution in water (1.5 L) with vigorous stirring. After 1.0 hr stirring, the slurry was extracted with EtOAc (3x750ml). The EtOAC extracts were combined, washed with 10% NH4OH (2x750ml) and brine, dried over anhydrous Na2S04 and evaporated to give a black gum. This was passed through a pad of silica gel (E. Merck 230-400 mash, 1.2 kg) eluting with EtOAC to give 40 g (80%) of Compound C as a tan solid.
13C-NMR (CD3OD) 40,84, 49.23, 51.62, 51.71 , 62.56, 101.42, 119.14, 120.99, 127.56, 129.66, 130.38, 132.71 , 134.86, 139.82, 156.29 ppm
D . (R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-4H-1 ,4-benzodiazepine
Compound D was prepared from Compound C by the following sequence: Compound C of Example 98, run in the absence of triethylamine and with purification by flash chromatography on silica with 4:1 hexanes:ethyl acetate; Compound D of Example 1 ; treatment with 4M HCl in 1 :1 dioxane:ethyl acetate. MS (M+H)+ 344.
E. (R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, ethyl ester, hydrochloride. Ethylchloroformate (0.023 mL, 0.24 mmol) was added to a solution of
Compound D (0.10 g, 0.22 mmol) and DIPEA (0.16 mL, 0.9 mmol) in dry methylene chloride (1 mL) at 0°C under argon. After stirring for 2.5 days the reaction was partitioned with NaHCO3 (5 mL) and CHCI3 (20 mL). The aqueous layer was extracted with CHCI3 (2 x 10 mL). The combined organic layers were washed with NaHC03, water and brine, dried over MgS04, filtered and concentrated. The product was purified on a flash column eluting with EtOAc (200 mL) and 19/1 CHCIg CH3OH (200 mL), treated with 1 N NaOH to remove acylation on imidazole, and treated with HCI/ether to afford Example 248 (0.047 g, 52 %).
MS (M+H)+ = 416.
1 H NMR (CD3OD): d 8.9 (d, 1 H, J = 16 Hz), 7.48-7.12 (m, 8H), 6.9 (m, 1 H), 5.0-4.4 (m, 5H), 4.8-3.7 (m, 3H), 3.4-3.2 (m, 2H), 2.89-2.7 (m, 2H), 1.03 (m, 3H).
Example 249
Figure imgf000213_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-8- yl]cyclohexanecarboxamide, dihydrochloride.
Methanesulphonyl chloride (0.024 mL, 0.38 mmol) was added to a heterogeneous mixture of Compound C of Example 246 (0.030 g, 0.054 mmol), DMF (0.2 mL), and triethylamine (0.2 mL) in dry methylene chloride (0.3 mL) at rt under argon. After stirring for 2.5 days another eq of mesylchloride was added. After stirring for 3 hr the mixture was diluted with NaHC03 and CHCI3, the layers were separated and the aqueous layer was extracted with chloroform (2 x 20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over MgS04, filtered and concentrated. The residue was purified on a silica flash column eluting with CHCI3, and 9/1 CHCI3/CH3OH (200 mL each), to afford Example 249 (5 mg, 17 %).
MS (M+H)+ = 522.
1 H NMR (CD3OD): δ 8.88 (s, IH), 7.5 (m, 2H), 7.3 (m, 5H), 7.05 (d, 1H, J = 8
Hz), 6.8 (d, 1 H, J = 8Hz), 4.8-4.2 (m, 5H), 3.6 ( m, 1 H), 3.2 (m, 1 H), 3.0 (m, 1 H), 2.7 (m, 1 H), 2.3 (m, 3H), 1.6-1.9 (m, 5H), 1.1-1.5 (m, 4H), 0.9 (m, 2H).
Example 250
Figure imgf000214_0001
(R)-7-Cyano-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5- tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, dihydrochloride.
A. (R)-7-Cyano-4-(ethenylsulfonyl)-2,3,4,5-tetrahydro-1 -
(1 H-imidazol-4-y»methyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine
2-Chloroethanesulfonyl chloride (1.85 g, 11.4 mmol) was added to a solution of Compound D of Example 248 (1.0 g, 3.79 mmol) and DIPEA (2.6 mL, 15.2 mmol) in dichloromethane (16 mL) at 0°C under argon. After stirring for 16 hr, the reaction was diluted with chloroform and aq NaHC03. The layers were separated, the aqueous layer was reextracted twice with chloroform. The combined organic extract was washed twice with NaHC03 and brine, dried over MgS04, filtered and concentrated. The product was purified on a silica flash column eluting with 75% followed by
50%hexanes/ethyl acetate to afford Compound A (0.31 g, 23 %). MS: (M+H)+ = 434. B. (R)-7-Cyano-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, dihydrochloride
Compound A (0.59 g, 1.36 mmol) in a 2M solution of dimethylamine in THF (15 mL, 30 mmol) was warmed in a sealed tube to 60°C for 16 hours. The reaction was concentrated and the residue was purified by preparative HPLC (gradient of 30-90% aqueous methanol with 0.1 % TFA). The purified TFA salt was converted to its HCl salt with HCI/ether and lyophilized to afford Example 250 (11 mg, 1.7%). MS: (M+H)+ = 479.
1 H NMR (CD3OD): d 8.9 (s, 1H), 7.5-7.2 (m, 8H), 6.9 (m, 1 H), 4.8-4.4 (m, 5H),
3.95 (m, 1 H), 3.4-3.1 (m, 5H), 3.0-2.7 (m, 8H).
Example 251
Figure imgf000215_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- [[2-(4-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, dihydrochloride. Example 251 was prepared from Compound A of Example 250 and morpholine as described for Example 250 (61%). MS: (M+H)+ = 521. 1H NMR (CD3OD): d 8.9 (s, 1H), 7.75-7.2 (m, 8H), 6.95 (m, 1 H), 5.0 -4.4 (m,
3H), 4.1-3.7 (m, 7H), 3.5-3.1 (m, 6H), 3.0 (m, 3H), 2.85 (m, 1 H), 2.55 (m, 1 H). Example 252
Figure imgf000216_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-methoxy- 3-methylbenzoyl)-1 H-1 ,4-benzodiazepin-8- yl]cyclohexanecarboxamide, dihydrochloride.
To a solution of Compound C of Example 246 (46 mg, 0.1 mmol) in DMF (1 mL) at rt under argon were added sequentially, 2-methoxy-3- methylbenzoic acid (20 mg, 0.12 mmol), DIPEA (0.09 L, 0.5 mmol), HOAt (16 mg, 0.12 mmol) and EDC (23 mg, 0.12 mmol). After 18 hr, NaOH (1 N, 1 mL) and MeOH (2 mL) were added. After 25 min, the volatiles were removed in vacuo and the residue was partitioned between chloroform (15 mL) and NaHCOg (10 mL). The organic layer was separated, dried and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% MeOH in chloroform to afford a white solid (42 mg, 83%) which was dissolved in MeOH (1 mL) and HCl in ether (1 N, 2 mL) was added. The mixture was concentrated in vacuo to afford Example 252 as a yellow solid (50 mg).
MS (M+H)+ = 502.3.
Example 253
Figure imgf000217_0001
8-[(Cyclohexylcarbonyl)amino]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-N-phenyl-1 H-1 ,4-benzodiazepine-4- carboxamide, dihydrochloride.
To a solution of Compound C of Example 246 (46 mg, 0.1 mmol) in DMF (1 mL) at rt under argon were added sequentially, phenylisocyanate (13 μL, 0.12 mmol) and DIPEA (0.09 mL, 0.5 mmol). After 18 hr, NaOH (1 N, 1 mL) and MeOH (2 mL) were added. After 25 min, the volatiles were removed in vacuo and the residue was partitioned between chloroform (15 mL) and water (10 mL). Some of the desired product that precipitated was filtered. The organic layer was separated and concentrated in vacuo. The residue was mixed with the solid obtained by filtration, dissolved in MeOH/TFA mixture and purified by reverse phase preparative HPLC eluting with 50%-90% aqueous MeOH containing 0.1% TFA. Appropriate fractions were collected and concentrated. The residue was treated with 1N HCl followed by concentration. After three treatments, the residue was dissolved in water and lyophilized to afford Example 253 as a yellow solid (30 mg, 55%).
MS (M+H)+ = 473.3.
Example 254
Figure imgf000218_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2- methylphenyl)sulfonyl]-1 H-1 ,4-benzodiazepin-8- yl]cyclohexanamide, dihydrochloride.
Example 254 was prepared as a yellow solid from Compound C of Example 246 and 2-methylbenzenesulfonyl chloride as described for Example 253, except that the quenched, evaporated reaction mixture was directly purified by preparative HPLC (29%). MS (M+H)+ = 508.2.
Example 255
Figure imgf000218_0002
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2- methoxyphenyi)carbonyl]-1 H-1 ,4-benzodiazepin-8- yl]cyclohexanamide, dihydrochloride. Example 255 was prepared as a pale yellow solid from Compound C of Example 246 and 2-methoxylbenzoic acid as described for Example 252. MS (M+H)+ = 488.3.
Example 256
Figure imgf000219_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- 0 (phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonic acid, ethyl ester, hydrochloride.
A. (R)-7-Cyano-1 ,2,3,5-tetrahydro-3-(phenylmethyl)-4H-1 ,4- benzodiazepine-4-sulfonic acid, ethyl ester 5 Ethyl chlorosulf onate (0.49 g, 3.41 mmol) was added to a solution of Compound C of Example 248 (0.3 g, 1.13 mmol) and DIPEA (0.78 mL, 4.55 mmol) in dichloromethane (8 mL) at 0°C under argon. After stirring for 16 hr as it warmed to rt, the mixture was diluted with chloroform and NaHC03. The layers were separated and the aqueous layer was extracted 0 with chloroform. The combined organic extracts were washed with
NaHCOg.water, 1N HCl and twice with brine, dried over MgS04, filtered and concentrated, to afford Compound A (0.54 g, 13 %). MS (M-H)- = 370.
B. (R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4- 5 ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonic acid, ethyl ester, hydrochloride.
Example 256 was prepared from Compound A as described for Compound D of Example 1 , using dichloroethane and 3A sieves. Purification by preparative HPLC followed by conversion to the HCl salt and o lyophilization afforded Example 256. MS (M+H)+ = 535. 1HNMR (400 MHz, CD3OD): d 8.9 (s, 1 H), 7.5-7.2 (m, 8H), 6.9 (d, 1 H, J = 8 Hz), 5-4.4 (m, 4H), 4.3 (m, 1H), 4-3.2 (m, 4H), 3.0 (m, 1H), 2.8 (m, 1H), 1.05 (t, 3H).
Example 257
Figure imgf000220_0001
(3R)-7-Bromo-1 -[cyano(1 H-imidazol-4-yl)methyl]-2,3,4,5- tetrahydro-4-(methylsulfonyl)-3-(pheny lmethyl)-1 H-1 ,4- benzodiazepine, monohydrochioride.
To a stirred solution of Compound C of Example 224 (390 mg, 1.0 mmol) in a mixture of acetonitrile, methanol and acetic acid (3 mL, 1 :1:1) was added 4-formylimidazole (100 mg, 1.04 mmol) followed by sodium cyanide (55 mg, 1.12 mmol). The mixture was stirred at room temperature for 2 days, quenched with saturated potassium carbonate (2 mL) and partitioned between ethyl acetate and 1 N NH4OH solution. The organic layer was separated and washed with brine, dried, and concentrated to give a solid (400 mg, 80%). A portion was converted to its HCl salt by dissoving in methanol, addition of 1 N HCl in ether, and removal of the solvent to afford Example 257.
TLC Rf = 0.50 (ethyl acetate, two spots) MS (M+H)+ 500 Example 258
Figure imgf000221_0001
(3R)-1-[2-Amino-1-(1 H-imidazol-4-yl)ethyl]-2,3,4,5-tetrahydro-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
To a stirred suspension of lithium aluminium hydride (95 mg, 2.5 mmol) in ether under argon at room temperature, was added a solution of the free base of Example 257 (250 mg, 0.5 mmol) in anhydrous THF. The mixture was stirred at room temperature for 8h and was diluted with THF, followed by ethyl acetate and ammonium hydroxide. The suspension was stirred at room temperature for 18h and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography (ethyl acetate/methanol/NH40H, 10:1 :0.1) on silica to give a semisolid (80 mg, 38%). A portion of it was converted to its HCl as described in Example 257. MS (M+H)+ 426
Example 259
Figure imgf000222_0001
(3R)-1-[2-(Dimethylamino)-1 -(1 H-imidazol-4-yl)ethyl]-2, 3,4,5- tetrahydro-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
To a stirred solution of the free base of Example 258 (20 mg) in methanol (1 mL) and acetic acid (0.5 mL) with sodium acetate (100 mg), was added 30 μL of formaldehyde (37% aq. solution), followed by NaCNBH3 (15 mg). The mixture was stirred for 15 min, additional formaldehyde (30 μL) and NaCNBH3 were added and the mixture was stirred for 30 min and diluted with ethyl acetate and quenched with 3 mL of NH40H solution. The organic layer was separated, washed with 1 N NH40H solution and brine, dried, and concentrated. The residue was converted to its HCl salt as described in Example 257 (23 mg). MS (M+H)+ 454.
Example 260
Figure imgf000223_0001
(3R)-1-[2-Amino-1 -(1 H-imidazol-4-yl)ethyl]-7-bromo-2,3,4,5- tetrahydro-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
To a stirred solution of the free base of Example 258 (20 mg) in chloroform (1.5 mL) was added tetrabutylammonium perbromide. The mixture was stirred at room temperature for 10 min and quenched with an aqueous solution of NaS2O3. The organic layer was separated and washed with chloroform. The combined organic layers were dried over MgS04 and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/methanol/NH4OH; 10:1 :0.1) to give a white solid (17 mg), which was converted to its hydrochloride salt as described in Example 257. MS (M+H)+ 504.
Example 2fil
Figure imgf000224_0001
(3R)-1-[2-(Dimethylamino)-1-(1 H-imidazol-4-yl)ethyl]-7-bromo- 2,3,4, 5-tetrahydro-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 261 was prepared from Example 260 as described for Example 259. MS (M+H)+ 532.
Example 262
Figure imgf000224_0002
7-Cyano-1 ,3,4,5-tetrahydro-1-(1-methyl-1 H-imidazol-5-ylmethyl)- 3-(phenylmethyl)-4-(phenylsulfonyl)-2H-1 ,4-benzodiazepin-2- one, monohydrochloride.
A. (R)-N-(2-amino-5-bromo-phenylmethyl)-N- (methanesulfonyl)-phenylalanine methyl ester
To a stirred solution of (R)-N-(2-aminophenylmethyI)-N- (methanesulfonyl)-phenylalanine methyl ester (prepared from D- phenylalanine methyl ester hydrochloride by reductive amination with 2- nitrobenzaldehyde followed by reaction with methanesulfonyl chloride in pyridine and reduction with stannnous chloride in ethyl acetate; 7.0 g, 16.5 mmol) in chloroform (75 mL) at room temperature was added tetrbutylammonium perbromide (7.1 g, 14.8 mmol) portionwise. The mixture was allowed to stir at room temperature for 30 min. Saturated NaHC03 solution was added, followed by solid Na2S2O3. The mixture was stirred for 1 hour, concentrated in vacuo, and the residue was partitioned between water and 50% ethyl acetate/hexanes. The organic layer was separated, washed with water, brine, dried, concentrated in vacuo. The residue was purified by flash column chromatography to give Compound A as an oil (4.5 g, 54%). MS (M+H)+ 503. [a]D20: + 29.6 ° (CHCI3, c = 0.25)
B. 7-Cyano-1 ,3,4,5-tetrahydro-3-(phenylmethyl)-4- (phenylsulfonyl)-2H-1 ,4-benzodiazepin-2-one
A solution of Compound A (2.05 g, 4.07 mmol) in N- methylpyrrolidinone (10 mL) in the presence of CuCN (1.1 g, 12.3 mmol) was heated at 195°C for 4 h. The mixture was cooled to room temperature and partitioned between NH4OH solution and methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried, and concentrated. The residue was crystalized from methanol to give Compound B as a brown solid (1.1 g, 65%). MS(M+H)+ 416. mp 222- 223°C.
C . 7-Cyano-1 ,3,4,5-tetrahydro-1 -(1 -triphenylmethyl-1 H- imidazol-4-ylmethyl)-3-(phenyimethyl)-4-(phenyisulfonyl)-2H- 1 ,4-benzodiazepin-2-one
To a stirred solution of Compound B (310 mg, 0.74 mmol), N- tritylimidazole-4-methanol (510 mg, 1.5 mmol) and triphenylphosphine (450 mg, 1.72 mmol) in toluene and dichloroethane (20 mLJ3 mL) at 60°C under argon, was added diethylazodicarboxylate (300 uL, 1.9 mmol). The mixture was stirred at 60°C for 1 h and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, concentrated in vacuo, and purified by flash column chromatography (ethyl acetate/hexanes 2:3) to give Compound C as an oil (450 mg, 82%). MS(M+H)+740. D. 7-Cyano-1 ,3,4,5-tetrahydro-1 -(1-methyl-1 H-imidazol-5- ylmethyl)-3-(phenylmethyl)-4-(phenylsulfonyl)-2H-1 ,4- benzodiazepin-2-one, monohydrochloride
To a stirred solution of Compound C (210 mg, 0.28 mmol) in THF at room temperature under argon, was added methyl trifluoromethylsulfonate
(35 μL, 0.31 mmol). The mixture was stirred at room temperature for 10 min.
Acetic acid (0.5 mL) and triethylsilane (0.25 mL) were added. The mixture was heated at 60°C for 30 min and partitioned between 1 N NaOH and ethyl acetate. The organic layer was separated and washed with brine, dried and concentrated in vacuo. The residue was purified by flash column chromatography to give the free base of Compound D an oil (100 mg, 71 %).
This was dissolved in methanol, and 1 N HCl solution in ether was added.
The solvent was removed to give Example 262 as a solid.
MS (M+H)+512. mp: 160°C
Example 263
Figure imgf000226_0001
7-Cyano-1 ,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(phenylsulfonyl)-2H-1 ,4-benzodiazepin-2-one, monohydrochloride.
To a stirred solution of Compound C of Example 262 (200 mg, 0.27 mmol) in CHCI3 at room temperature under argon, was added trifluoroacetic acid (1 mL), followed by triethylsilane (0. 5 mL). The mixture was stirred at room temperature for 2 h and partitioned between 1 N NH40H and ethyl acetate. The organic layer was separated and washed with brine, dried and concentrated in vacuo. The residue was purified by flash column chromagraphy (ethyl acetate, methanol; 95:5) to give the free base of Example 263 as an oil (110 mg, 82%). This was dissolved in methanol, and 1 N HCl solution in ether was added. The solvent was removed to give Example 263 as a solid. MS (M+H)+498. mp: 195°C
Example 264
Figure imgf000227_0001
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 7-Bromo-2,3,4,5-tetrahydro-3-(2-phenylethyl)-1 H-1 ,4- benzodiazepine
Compound A was prepared from D,L-homoPhe and 6-bromoisatoic anhydride as described in the following sequence: Compound A of Example 80, except that DMF was used instead of pyridine, and heating was at 50°C for 24 hours; Compound B of Example 80; Compound C of Example 80.
B. 7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-(2- phenylethyl)-1 H-1 ,4-benzodiazepine
Compound A (100 mg, 0.30 mmol) was dissolved in THF (5 mL) and DIEA (211 μL, 1.21 mmol) was added followed by methanesulfonyl chloride (94 μL, 1.21 mmol). The solution was stirred for 30 min, concentrated, redissolved in ethyl acetate (50 mL) and washed with water (3X20 mL). The organic layer was dried (Na2S04) and concentrated to yield Compound B as a light brown glass. C . 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
4-(methylsulfonyl)-3-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride
Compound C and 4-formylimidazole were dissolved in 1 ,2-DCE (5 mL) and acetic acid (0.5 mL) and sodium triacetoxyborohydride was added. The mixture was stirred at 50°C for 2h and saturated NaHCθ3 (5 mL) was added. The mixture was concentrated and the residue was partitioned between water (20 mL) and ethyl acetate (20mL). The organic layer was washed with water (10mL), brine (10 mL), dried (MgS04), concentrated and purified by preparative HPLC (gradient of aq methanol, 0.1% TFA). Appropriate fractions were combined, concentrated and lyophilized. The lyophilate was dissolved in methanol (0.5 mL) and 1N HCl (5mL). The mixture was concentrated and lyophilized. This procedure was repeated to provide Example 264 as a white solid (15 mg, 19%). MS (M+H)+ 490.
Example 265
7-Bromo-3-[(3-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine. dihydrochloride.
A. 2-[2-(1 ,1 -dimethyl-ethoxycarbonylamino)-3-(3-chloro- phenyl)-propylamino])-5-bromobenzoic acid
N-Boc-3-chloro-phenylalaninal (800 mg, 2.8 mmol) and 2-amino-5- bromobenzoic acid (660 mg, 3.06 mmol) were dissolved in MeOH (10 mL). Molecular sieves (3 A, 7.0 g) and glacial acetic acid (0.2 mL) were added and the mixture was stirred for 30 min. Sodium cyanoborohydride (200 mg, 2.99 mmol) was added portionwise over 30 min. The mixture was stirred for 16 h, cooled to 0°C and saturated NaHCO3 (30 mL) was slowly added. The mixture was stirred for 30 min, concentrated and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (100 mL), brine (100 mL), dried (MgSθ4), and concentrated. Preparative HPLC (gradient of aq methanol, 0.1% TFA) afforded Compound A as a clear oil (100 mg, 7%). MS (M+H)+ 481.
B. 2-[2-amino-3-(3-chloro-phenyl)-propylamino])-5- bromobenzoic acid
Compound A (100 mg, 0.21 mmol) was stirred in dimethyl sulfide (0.1 mL) and 4N HCl in dioxane (10 mL) for 40 min. The mixture was concentrated, redissolved in methylene chloride (20 mL) and concentrated. This latter procedure was repeated three times to yield Compound B as a clear glass.
C . 7-Bromo-3-[(3-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4- benzodiazepine, dihydrochloride. Compound C was prepared as a white solid from Compound B by the following sequence: Compound B of Example 80; Compound C of Example 80; Compound B of Example 264; Compound C of Example 264. MS (M+H)+ 510.
Example 266
Figure imgf000229_0001
(R)-7-Bromo-3-(cyclohexyimethyl)-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Example 266 was prepared as a white solid from D-N-Boc- cyclohexylaianinal as described in Example 265. MS (M+H)+ 510.
Example 267
Figure imgf000230_0001
7-Bromo-3-[(2-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 267 was prepared as a white solid from D,L-N-Boc-2- chlorophenylalaninal as described in Example 265. MS (M+H)+ 510.
Example 268
Figure imgf000230_0002
(S)-7-Bromo-3-(cyclohexylmethyl)-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Example 268 was prepared as a white solid from L-N-Boc- cyclohexylalaninal as described in Example 265. MS (M+H)+ 482.
Example 269
Figure imgf000231_0001
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[(4- methoxyphenyl)methyl]-4-(methylsulfonyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 269 was prepared as a white solid from D,L-N-Boc-4- methoxy-phenylalaninal as described in Example 265. MS (M+H)+ 506.
Example 270
Figure imgf000231_0002
4-Acetyl-7-bromo-3-[(2-chlorophenyl)methyl]-2,3,4,5-tetrahydro- 1 -(1 H-imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Example 270 was prepared as a white solid from 7-bromo-3-[(2- chlorophenyl)methyl]-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine as described in Compounds D and E of Example 80. MS (M+H)+ 475.
Example 271
Figure imgf000232_0001
4-Acetyl-7-bromo-3-[(3-chlorophenyl)methyl]-2,3,4,5-tetrahydro- 1 -(1 H-imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 271 was prepared as a white solid from 7-bromo-3-[(3- chlorophenyl)methyl]-2,3,4,5-tetrahydro-1 H-1 ,4-benzodiazepine as described in Example 270. MS (M+H)+ 475.
Example 272
Figure imgf000233_0001
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-yimethyl)-3-[(4- hydroxyphenyl)methyl]-4-(methylsulfonyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
To a solution of Example 269 (30 mg, 0.059 mmol) in a mixture of dichloromethane (5 mL) and 1 ,2-dichloroethane (5 mL) was added a solution of BBr3 (1M in dichloromethane, 0.5 mL). The mixture was stirred for 16h and 5% ammonium hydroxide (10 mL) was added. The mixture was stirred for additional 1h, concentrated and the residue purified by preparative HPLC (gradient of aqueous methoanol with 0.1 % TFA). Appropriate fractions were combined, concentrated and lyophilized. This lyophilate was dissolved in methanol (0.5 mL) and 1N HCl (5mL). This mixture was concentrated and lyophilized. This procedure was repeated to provide Example 272 as a white solid (20 mg, 60%). MS (M+H)+ 490.
Example 273
Figure imgf000234_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-7-phenyl-3-(3-pyridinylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 273 was prepared as a light yellow solid from D- pyridylalanine and Compound B of Example 226 using the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound C of Example 264. MS (M+H)+ 474.
Example 274
Figure imgf000234_0002
2,3,4,5-Tetrahydro-8-(hydroxymethyl)-1-(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 8-[2,3,4,5-Tetrahydro-1 H-1 ,4-benzodiazepin-2,5-dionyl]- carboxyiic acid
A mixture of 7-carboxyisatoic anhydride (prepared from triphosgene and 4-carboxylic-2-amino-benzoic acid, 20 g, 0.09 mol) and ethyl glycine hydrochloride (13.5 g, 0.097 mol) in anhydrous pyridine (200 mL) was refluxed 30 hrs and cooled to rt. The pyridine was evaporated and the residue was washed with water followed by EtOAc. The solid was dried under reduced pressure to give Compound A (17.5 g, 88%) as a white solid.
B. 2,3,4,5-Tetrahydro-8-(hydroxymethyl)-1 H-1 ,4- benzodiazepine
Borane (1.0 M in THF, 1L) was added to a suspension of Compound A (10 g, 45 mmol) in ethylene glycol dimethyl ether (10 mL). The suspension was stirred at r.t. for 1 hr, refluxed for 8 hrs, cooled to 0° and quenched with 6N HCl (20 mL). The solvent was evaporated, the residue dissolved in water (30 mL) and the mixture neutralized with sat. Na2C03 and evaporated. The residue was evaporated from methanol and purified by flash column chromatography (10% MeOH, 1% NH4OH in CH2CI2) to provide Compound B as a white solid. MS (M+H)+ 179.
C . 2,3,4,5-Tetrahydro-8-(hydroxymethyl)-1-(1 H-imidazol-4- ylmethyl)-4-(1 -naρhthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride Example 274 was prepared as an off white solid from Compound B as described for Compound F of Example 41 , with chromatography using 5% MeOH/0.5% NH4OH/methylene chloride, and Compound D of Example 1 , with purification by prep HPLC before formation of the HCl salt. MS (M+H) 413.
Example 275
Figure imgf000236_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-8-(phenoxymethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A solution of Example 274 (0.38 g, 0.9 mmol) and Boc20 (1.2 g, 5.4 mmol) in CH2CI2 (10 mL) was stirred for 48 hrs and evaporated. The residue was purified by flash chromatography (4% MeOH in CH2CI2) to give the protected imidazole analog as a white solid (0.190 g, 40%). A mixture of a portion of this material (42 mg, 0.08 mmol), Ph3P (28 mg, 0.1 mmol), phenol (30 mg, 0.3 mmol) and diethylazodicarboxylate (0.05 mL, 0.3 mmol) in THF (7 mL) was stirred for 48 hrs. under N2. 1 N HCl (5 mL) was added. The mixture was stirred for 1 hr and evaporated. The residue was treated with 6M HCL, extracted with CH2Cl2 (2X10 mL) and the aqueous layer evaporated to give a solid which was purifed by prep HPLC (gradient of aqueous methanol with 0.1% TFA) and converted into its HCl salt by lyophilization from 1 M HCl (5 mL) to give Example 275 as a white solid (10 mg, 24%)
MS (M+H)+ 489.
Example 276
Figure imgf000237_0001
N-Cyclohexyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8- carboxamide, dihydrochloride.
A. 2,3,4,5-Tetrahydro-8-(hydroxymethyl)-1 H-1 ,4-bis-(1- naphthalenylcarbonyl)-benzodiazepine Naphthoyl chloride (18 mL g, 110 mmol) was added to a solution of compound B of Example 274 (24 g, 29 mmol) in pyridine (150 mL) and the resulting solution was stirred for 10 hrs and poured into ice-water. The resulting precipitate was filtered and the solid was washed with water and subjected to flash chromatography (3% MeOH in CH2CI2) to provide the trinaphthoate as a yellow solid (8.4 g, 45%). A portion of this material (5.63 g, 87 mmol) in MeOH (60 mL) was stirred with 1 M NaOMe in MeOH (40 mL) for 10 hrs and evaporated. The residue was dissolved in CH2CI2 (150 mL) and the solution was washed with H2O (50 mL) and 1N HCL (50 mL), dried over Na2S04 and evaporated. Purification by flash chromatography (5% MeOH in CH2CI2) provided Compound A as a white solid (3.8 g, 89%). MS (M+H)+ 486.
B. 2,3,4,5-Tetrahydro-1-(1-naphthalenylcarbonyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8-carboxylic acid Jones reagent (5% CrO3 in 10% H2S04 in H2O, 15 mL) was slowly added to a solution of Compound A (2.7 g, 5.6 mmol) in acetone (50 mL) at 0°C. The solution was stirred for 1hr. at r.t. The excess Cr03 was destroyed by adding iPrOH. The aqueous solution was extracted with CH2CI2 (3X 100 L). The combined organic phases were dried over Na2S03 and evaporated to give a solid which was purified by flash chromatography (5% MeOH in CH2CI2) to provide Compound B as a solid (2.30 g, 82.7%). MS (M+H)+ 499.
C . 2,3,4,5-Tetrahydro-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4- benzodiazepine-8-carboxylic acid
A mixture of Compound B (1.02 g, 2 mmol) in MeOH (40 mL) was refluxed with KOH (7.75 g, 138 mmol) in H2O (10 mL) for 40 hrs. The MeOH was evaporated and aqueous solution was neutralized with cone. HCl. The resulting precipitate was filtered and washed with H20. The solid was dried to provide Compound C as a white solid (0.635 g, 90%). MS(M+H)+ 347.
D . N-Cyclohexyl-2,3,4,5-tetrahydro-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8-carboxamide
A solution of cyclohexylamine (0.32 g, 3.2 mmol) and diisopropylethylamine (1 mL, 5.7 mL) in DMF (1 mL) was added to a solution of EDC (0.12 g, 0.62 mmol), HOBT (0.13 g, 0.9 mmol) and Compound C (20 mg, 0.06 mmol) in DMF (5 mL). The solution was stirred for 24 hrs and evaporated. The residue was dissolved in EtOAc (20 mL) and the solution was washed with sat. NaHC03, 1N HCl (5 mL), dried over Na2S04 and evaporated to give Compound D as a pale yellow solid (40 mg).
E. N-Cyclohexyl-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8- carboxa ide, dihydrochloride Compound E was prepared from Compound D as described for
Compound D of Example 1 , with purification by prep HPLC before formation of the HCl salt. MS (M+H)+ 508.
Example 277
Figure imgf000239_0001
N-(Cyclohexylmethyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8- carboxamide, dihydrochloride.
Example 277 was prepared as an off white solid from Compound C of Example 276 and cyclohexylamine as described in Compounds D and E of Example 276. MS (M+H)+ 522.
Example 278
Figure imgf000239_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 naphthalenyl-carbonyl)-N-(phenylmethyl)-1 H-1 ,4- benzodiazepine-8-carboxamide, dihydrochloride. Example 278 was prepared as an off white solid from Compound C of Example 276 and benzylamine as described in Compounds D and E of Example 276.
MS (M+H)+ 517.
Example 279
Figure imgf000240_0001
(R)-4-Acetyl-7-[2-[(dimethylamino)methyl]phenyl]-2, 3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A. 2-[(R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-2,5-dion-7-yl]-benzaidehyde Compound A was prepared as a yellow solid from Compound A of
Example 224 and 4-formylbenzeneboronic acid as described for Compound A of Example 12, with THF as solvent, refluxing for 10 hours, and extractive workup. MS (M+H) + 371.
B. (R)-7-(2-(Dimethylaminomethyl)-phenyl)-2, 3,4,5- tetrahydro-3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-2,5-dione
A solution of Compound A and dimethylamine (1.0 M in THF, 10 mL) in 1 :10/AcOH:CH2CI2 (20 mL) was stirred for 1 hr. NaBH(OAc)3(2.0 g) was added. Stirring was continued for 14 hrs. The solvent was evaporated and residue was treated with 1 N NaOH (10 mL). The aqueous layer was extracted with 10% iPrOH in CH2CI2. The organic phase was dried and evaporated to give a pale yellow solid which was purified by flash chromatography (10% MeOH, 1 % Et3N in CH2CI2 ) to provide Compound B as a white solid (1.13 g, 98%). MS(M+H)+ 400.
C . (R)-7-(2-(Dimethylaminomethyl)-phenyl)-2, 3,4,5- tetrahydro-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
A solution of Compound B (1.13 g) in dry THF was treated with LAH (1.0 M in THF, 15 mL) at 0° C. The solution was refluxed for 10 hrs, cooled to 0°C and H20 (5 mL) was added followed by THF (10 mL) and 20% NaOH (5 mL). The THF solution was decanted and the solid was washed with THF. The combined THF solutions were evaporated and the residue dissolved in CH2CI2 (20 mL). The solution was evaporated to give Compound C as a pale yellow solid (0.7 g, 67%). MS (M+H)+ 372.
D . (R)-4-Acetyl-7-[2-[(dimethylamino)methyl]phenyl]-2, 3,4,5- tetrahydro-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
Acetyl chloride (0.03 mL, 1.1 eq.) in CH2CI2 (0.3 mL) was added to a solution of Compound C (0.155 g, 0.41 mmol) and DIEA (0.4 mL, 2.7 mmol) in CH2CI2 (10 mL). The mixture was stirred 20 minutes and evaporated. The residue was dissolved in EtOAc and the solution was washed with sat. NaHCOg, dried over Na2SO4 and evaporated to give Compound D as an oil (0.14 g, 84%).
E . (R)-4-Acetyl-7-[2-[(dimethylamino)methyl]phenyl]-2, 3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Compound E was prepared from Compound D as described for Compound E of Example 276. MS (M+H)+ 492.
Figure imgf000242_0001
(R)-4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-7-Cyano-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-[(1 ,1 - dimethylethoxy)-carbonyl]-1 H-1 ,4-benzodiazepine Compound A was prepared as a white solid from Compound C of
Example 248 as described for Compound A of Example 4, with stirring in THF for 10 hours.
B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethy l)-3-(phenylmethyl)-4-[(1 ,1 -dimethylethoxy)-carbonyl]- 1 H-1 ,4-benzodiazepine
Compound B was prepared from Compound A as described for Compound D of Example 1.
C . (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
Compound C was prepared from Compound B by treatment with 4M HCl in 4:1 ethyl acetate:dioxane. MS(M+H)+244.
D . (R)-4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-
4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride
Compound D was prepared from Compound C by treatment with DIEA, EDC, HOBT and acetic acid in DMF for 14 hours. Purification by prep HPLC (gradient of aqueous methanol with 0.1 % TFA) and conversion into its HCl salt by lyophilization from 1M HCl afforded Example 280 as a solid. MS (M-H)+ 386.
Example 281
Figure imgf000243_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethy l)-4-(1 oxobutyl)-3-(phenyimethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 281 was prepared as a solid from Compound C of Example 280 and butyric acid as described for Compound D of Example 280. MS (M-H)+ 414.
Figure imgf000243_0002
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(2- methyl-1-oxopropyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. Example 282 was prepared as a solid from Compound C of Example 280 and isobutyric acid as described for Compound D of Example 280.
MS (M-H)+ 414.
Example 283
Figure imgf000244_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-pyridinylacetyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 283 was prepared as an off white solid from Compound C of Example 280 and 2-pyridylacetic acid as described for Compound D of Example 280. MS (M-H)+ 464.
Example 284
Figure imgf000245_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-7-Cyano-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2- thienylsulfonyl)-1 H-1 ,4-benzodiazepine 2-Thiophenesulfonyl chloride (34.56 g, 0.19 mol) in CH2CI2 (200 mL) was added to a solution of Compound C of Example 248 (37.4 g, 0.142 mol) and DIEA (38 mL, 0.23 mol) in CH2CI2 (500 mL) at rt. The solution was stirred for 48 hrs and evaporated. The residue was partitioned between CH2CI2 (500 mL) and saturated NaHCO3 (2x500 mL). The organic layer was dried (Na2S04) and evaporated. The residual yellow oil was purified by flash chromatography (20% followed by 50%ethyl acetate/hexanes) to provide Compound A as a yellow solid (55 g, 95%).
B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A mixture of Compound A (55 g, -0.134 mol) and 4- formylimidazole (51 g, 0.53 mol) in AcOH/CH2CICH2CI (140 mL/600 mL) was stirred for 50 min at 55°C under N2. NaBH(OAc)3 (total: 72 g, 0.34 mol) was added over 15 hrs (every 1.5 to 2 hrs, average about 6 g was added) until HPLC analysis showed the absence of Compound A. MeOH (250 mL) was added and the solvent was evaporated. The residue was stirred with H20 (100 mL), then 4% NaOH (800 mL) for 30 min. The aqueous solution was extracted with ethyl acetate (2x800 mL). The combined organic layers were washed with 5% NaOH (800 mL) and dried over Na2S04. Evaporation of solvent gave an oil (85g) which was purified by flash chromatography (silica, 5% MeOH in EtOAc) to provide 70 g of a wet solid. HCl (1.0 M in ether, 400 mL, 0.4 mol) was added to a solution of the solid in EtOAc (600 mL). The resulting suspension was stirred for 20 min and evaporated. The residue was washed with EtOAc (2x500 mL) and ether (2x100 mL) and dried under high vacum to provide Compound B (63 g, 83%) as an off white solid. MS (M+H)+ 490.
1 H-NMR (CD3OD, 300 MHz) δ 2.90 (m, 2H), 3.15 (m, 2H), 3.90 (m, 1H), 4.3 to 5.1 (m, 4H), 6.40 (d, 7Hz, 1 H), 7.0 to 7.6 (m, 11H), 8.90 (s, 1H).
Examples 285-295
Examples 285-295 were prepared from Compound C of Example 248 (Exs 285, 286, 291 , 292, 293, 294, 295), Compound B of Example 224 (Exs 287, 288) or Compound B of Example 232 (Exs 289, 290) and the appropriate sulfonyl chloride as described for Example 284.
Example
285
286
287 m/z 501
(M+H)
Figure imgf000247_0001
288 m/z 539 (M+H)
289 m/z 535 (M+H)
Figure imgf000248_0001
mono y roc or e. - 215356
290
291
Figure imgf000248_0002
Figure imgf000249_0001
mono y roc or e. BMS-218735
295 (R)-N-[5-[[7-cyano-2,3,4,5- tetrahydro-1-(1 H-imidazol-
4-ylmethyl)-3-
(phenyimethyl)-
1 H-1 ,4-benzodiazepin-4- yl]sulfonyl]-4-methyl-2-
Figure imgf000249_0002
thiazolyl]acetamide, dihydrochloride. BMS-
218736
Figure imgf000250_0001
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
A. 4-Acetyl-2,3,4,5-tetrahydro-1 -trif luoroacetyl-3- (phenylmethy l)-7-bromo-1 H-1 ,4-benzodiazepine Acetyl chloride (35mL, 0.47 mmol) was added to a solution of
Compound B of Example 75 (0.32 mmol, 100 mg) and NEt3 (220 L, 1.58 mmol) in 5 mL of CH2CI2at 0°C. After 5 minutes, trifluoroacetic anhydride (0.63 mmol, 90 mL) was added, and the reaction was stirred for an additional 10 minutes, concentrated and the residue purified by flash chromatography (50%EtOAc/Hexanes) to afford Compound A as a white solid (140 mg, 98% for two steps). MS (M+H) 455.
B. 4-Acetyl-2,3,4,5-tetrahydro-1 -trif luoroacetyl-3- (phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine A mixture of Compound A (0.27 mmol, 124 mg), 4- tributylstannylpyridine (0.54 mmol, 200 mg) and 15 mol% Pd(PPh3)4 (47 mg) in 3 mL of toluene was degassed and heated to reflux under argon. After 16 hours, the reaction was concentrated and purified by flash chromatography (10%EtOAc/Hexanes) to isolate Compound B as a yellow oil (60 mg, 49%). MS (M+H) 454. C . 4-Acetyl-2,3,4,5-tetrahydro-3-(pheny lmethyl)-7-(4- pyridinyl)-1 H-1 ,4-benzodiazepine
NaOH (5 drops of 2N NaOH aqueous solution) was added to a solution of Compound B (60 mg, 0.13 mmol) in 3 mL MeOH and the mixture was maintained at rt for 30 minutes, concentrated and partitioned between 2N NaOH (5 mL) and 10%isopropanol-CH2CI2 (5 mL). The aqueous layer was extracted 3 times with 10%isopropanol-CH2CI2 and the combined organic layers were dried over Na2S04 and concentrated to afford Compound C.
D . 4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride
To a mixture of Compound D in 2 mL of 1 :1 AcOH:CICH2CH2CI was added 4-formylimidazole (0.39 mmol, 38 mg) and NaBH(OAc)3 (0.39 mmol, 83 mg). The mixture was heated at 50°C for 4 hours, concentrated and partitioned between 2N NaOH and 10%isopropanol/CH2CI2 (5 mL). The aqueous layer was extracted 3 times with 10%isopropanol-CH2CI2 and the combined organic layers were dried over Na2S04, concentrated and purified by prep HPLC (gradient of aqueous methanol with 0.1% TFA). The TFA salt was converted to the HCl salt with 1 N HCl to afford Example 296 as a yellow solid (32 mg, 49% from Compound B). MS (M+H) 438.
Example 297
Figure imgf000251_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-phenyl-1 ,2- dioxoethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride. Example 297 was prepared as a yellow solid from 7-bromo-1 ,4- benzodiazepine (see Example 11) and benzoylformic acid by the following sequence: Example 252, in 10:1 methylene chloride:DMF and with chromotography with 50%EtOAc/hexanes; treatment with trifluoracetic anhydride and workup as described in Compound A of Example 296; Compounds B, C and D of Example 296. M+H (438).
Example 298
Figure imgf000252_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4- [2-(trif luoromethoxy)benzoyl]-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 298 was prepared as a yellow solid from 2- (trifluoromethoxy)-benzoic acid as described for Example 297. MS (M+H) 494.
Example 299
Figure imgf000253_0001
(R)-2,3,4,5-Tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4- (methylsulfonyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
A. (R)-2,3,4,5-Tetrahydro-4-(methylsulfonyl)-7-phenyl-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine Mesyl chloride (0.12 ml, 1.6 mmol) was added dropwise to a solution of Compound D of Example 226 (0.50 g, 1.3 mmol) and DIEA (0.78 ml, 4.5 mmol) in methylene chloride (20 ml) at -78°C. The mixture was allowed to warm to room temperature and stirred for 16h, quenched with 10% NaHCO3 (100 ml) and extracted with ethyl acetate (3X150 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography (5/2 hexane/ethyl acetate) to afford Compound A (0.52 g, 100%) as a yellow solid.
B. 1 -[1 ,1-Dimethylethoxycarbonyl]-4- imidazolecarboxaldehyde
Di-tert-butyl dicarbonate (55.4 g, 254 mmol) was added to a suspension of 4-formyi imidazole (20.0 g, 208 mmol) and DIEA (36.2 ml, 208 mmol) in 400 ml of methylene chloride at room temperature. The mixture was heated to 40°C upon which it became a clear solution and was stirred 16 h, cooled to room temperature, quenched with saturated NaHCO3 (200 ml) and extracted with CH2CI2 (3x400 ml). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by flash chromatography (5-50% ethyl acetate/hexane) to afford Compound B (35.2 g, 87%) as a white solid. MS: (M+NH4+CH3CN)+ 256
C. 1 -Methyl-5-imidazolecarboxaldehyde Methyl trifiate (22.3 ml, 197 mmol) was added slowly to a solution of
Compound B (35.1 g, 179 mmol) in CH2CI2 (740 ml) at -78°C. The mixture was allowed to warm to room temperature slowly and stirred 16h. The resultant white precipitate was quenched portionwise with a saturated solution of potassium carbonate (112 g/100 ml HzO) at room temperature. The biphasic solution was stirred at room temperature for 30 minutes. The phases were separated and the aqueous layer was extracted with 9/1 CH2CI2 / iPrOH (4X300 ml). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19/1 CHCL MeOH) to afford Compound C (17.4 g, 88%) as a white solid. MS (M+H)+ 111
D . (R)-2,3,4,5-Tetrahydro-1-[(1-methyl-1 H-imidazol-5- yl)methyl]-4-(methylsulfonyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine Compound C (0.065 g, 0.59 mmol) was added to a solution of
Compound A (0.23 g, 0.59 mmol) and 3A molecular sieves in 1/1 DCE: acetic acid (4 ml) and the mixture was stirred at 70°C for 1h. Sodium triacetoxyborohydride (0.13 g, 0.59 mmol) was added and the mixture was stirred at 70°C for 30 minutes. The latter procedure was repeated two more times. The mixture was cooled to room temperature, diluted with methylene chloride (10 ml), filtered and the filtrate was concentrated under vacuum. The residue was diluted with 25% NH4OH (100 ml) and stirred at room temperature for 10 minutes. The solution was extracted with CH2CI2 (3X100 ml), the combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by preparative HPLC (10-90% aq MeOH with 0.1 % TFA) and the appropriate fractions were pooled and concentrated under vacuum. The residue was evaporated from CH3OH (5 ml) and 1N HCl (3 ml) four times. The residue was dissolved in CH3CN (3 ml) and water (3 ml) and lyophilized to afford Example 299 (0.26 g, 80 %) as a white solid, mp: 106-114°C MS (M+H)+487 [a]D = + 91° (c = 0.35, CH3OH) Elemental analysis for C28H30N4O2S-HCI-0.9 H2O Calc: C, 57.88; H, 5.17; N, 9.06; Cl, 4.59; S, 5.18 Found: C, 57.88; H, 5.49; N, 9.14; Cl, 4.64; S, 5.31
Example 300
Figure imgf000255_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (phenylacetyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
To a refluxing solution of (R)-7-cyano-2,3,4,5-tetrahydro-4- (phenylacetyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (prepared from Compound C of Example 248 by EDC/HOAt coupling with phenylacetic acid, 0.100 g, 0.26 mmol) and 4-formylimidazole (0.025 g, 0.26 mmol) in AcOH (0.3 mL) and dichloroethane (0.5 mL) with 3A sieves was added sodium triacetoxyborohydride (0.055 g, 0.26 mmol). The mixture was stirred 16 hr, and then for 3 days, with additional aldehyde and sodium triacetoxyborohydride (3 x 1 eq each) added each day. The mixture was diluted with CHCI3 (10 mL), NH4OH (5 mL) and NaHC03 (5 mL), and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCIg (2 x 20 mL). The combined organic extracts were washed with NaHC03, water and brine, dried over MgS04, filtered and concentrated. The product was purified by preparative HPLC (gradient of 20-90% aqueous methanol with 1 % TFA) and the HCl salt formed to afford Example 300 as a light yellow solid (4 mg, 3%). MS (M+H)+ = 462+ Example 301
Figure imgf000256_0001
4-(2-Benzothiazolyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride.
A. 4-(2-Benzothiazolyl)-2,3,4,5-tetrahydro-7-phenyl-1 H-1 ,4- benzodiazepine
Chlorobenzothiazole (0.41 mmol, 53 mL) was added to a solution of Compound B of Example 12 (0.34 mmol, 100 mg) and triethylamine (1.36 mmol, 190 mL) in DMF (1.0 mL) and the reaction was maintained at 60°C. After 1 hr, additional 2-chlorobenzothiazole (60 mL) was added. After 2 hrs, the reaction was quenched with 2N NaOH (10 mL), extracted (2x10 mL) with CH2CI2, dried over Na2S04 and concentrated to afford Compound A.
B. 4-(2-Benzothiazolyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol- 4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride
4-Formylimidazole (0.68 mmol, 65 mg) and NaBH(OAc)3 (0.51 mmol, 108 mg) was added to a solution of Compound A in 1 :1 AcOH/(CH2CI)2 (2 mL). The mixture was stirred for 1 hr, quenched with 5 mL sat'd NaHCOg, diluted with 2N NaOH (50 mL) and extracted (2X25 mL) with 10% IPA CH2CI2. The combined organic extracts were dried over Na2S04, evaporated and the residue purified by flash chromatography (94 mg, 50% yield in two steps). Lyophilization from 1 N HCl afforded Example 301 as a gray solid.
MS (M+H)+ 438 Example 302
Figure imgf000257_0001
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)- 7-(3-pyridinyl)-4-(trif luoroacety l)-1 H-1 ,4-benzodiazepine, trihydrochloride.
A. 2,3,4,5-Tetrahydro-3-(phenyimethyl)-7-bromo-1 ,4- bis(trif luoroacety l)-1 H-1 ,4-benzodiazepine (CF3CO)2O (7.25 mmol, 1.0 mL) was added to Compound B of
Example 75 (1.61 mmol, 510 mg) and triethylamine (9.66 mmol, 1.35 mL) in CH2CI2 (10 mL) at RT. After 30 minutes, the reaction was concentrated and purifed by flash chromatography to provide Compound A as a white solid (770 mg, 94%). MS (M-H)+ 507.
B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenyimethyl)-7-(3-pyridinyl)-4-(trifluoroacetyl)-1 H-1 ,4- benzodiazepine, trihydrochloride
Example 302 was prepared as a yellow solid from Compound A by the following sequence: Compound B of Example 296, using 3- tributylstannylpyridine; Compound C of Example 296; Compound D of Example 296. MS (M+H)+ 492. Example 303
Figure imgf000258_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-7-(3-pyridinyl)-1 H-1 ,4- benzodiazepine, trihydrochloride.
A. 2,3,4,5-Tetrahydro-3-(phenylmethyl)-7-(3-pyridinyl)-1 H- 1 ,4-benzodiazepine Solid KOH (150 mg) was added to a solution of 2,3,4,5-tetrahydro-
3-(phenylmethyl)-7-(3-pyridinyl)-1 ,4-bis(trifluoroacetyl)-1 H-1 ,4- benzodiazepine (prepared as described in Compound B of Example 302; 100 mg, 0.2 mmol) in MeOH (4 mL). The solution was stirred at 50°C for 3 hrs, concentrated, diluted in 2N NaOH (15 mL), and extracted (3X5 mL) with 10% IPA/CH2CI2 to afford 60 mg of Compound A.
B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-7-(3-pyridinyl)-1 H-1 ,4- benzodiazepine, trihydrochloride Methanesulfonyl chloride (0.39 mmol, 30 mL) was added to a mixture of Compound A (0.086 mmol, 27 mg) and DIEA (0.86 mmol, 150 mL) in CH2CI2 (1.0 mL). The mixture was stirred for 1 hour, concentrated, diluted in 2N NaOH (10 mL) and extracted (2X5 mL) with 10% IPA/CH2CI2. The solution was dried over Na2S04 and concentrated. The residue was dissolved in 1 :1 AcOH:(CH2CI)2 (2 mL). 4-Formyiimidazole (0.69 mmol, 66.3 mg) and NaBH(OAc)3 (0.69 mmol, 146 mg) were added and the mixture was heated at 50°C for 16 hrs, concentrated, diluted in 2N NaOH (20 mL)/sat'd NH4OH (5mL) and extracted (2X5 mL) with 10% IPA/CH2CI2. The combined organic extracts were concentrated and purified by prep HPLC (gradient of aqueous methanol with 0.1 %TFA). Appropriate fractions were pooled, evaporated and the TFA salt was converted to the HCl salt with 1 N HCl to afford Example 303 as a yellow solid (5 mg, yield in 3 steps: 9%). MS (M+H)+ 474
Example 304
Figure imgf000259_0001
7-Bromo-3-[(1 ,1 -dimethylethoxy)methyl]-1 ,2,3,4-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-5H-1 ,4-benzodiazepin-5-one.
A. 2-[(2-(fluorenylmethoxycarbonylamino)-3-(1 ,1 - dimethylethoxy)propyl)amino]-5-bromo-benzoic acid A solution of D,L-Fmoc-(0-tBu)-serinal (prepared by LAH reduction of D,L-Fmoc-Ser(tBu)-N(Me)OMe; 18 g, 49 mmol), bromoanthranilic acid (19g, 88 mmol) and glacial acetic acid (2 mL) in dry methanol (5 mL) and THF (40 mL) was stirred for 10 minutes followed by the addition of NaBH3CN (5.5 g,88 mmol) over 1 hour. Stirring was continued for 1 h. The precipitated product was filtered, washed with water and dried under high vacuum to give 25g (89.4%) of Compound A as a white solid. (M+H)+ 569.
B. 7-Bromo-3-[(1 ,1 -dimethylethoxy)methyl]-1 ,2,3,4- tetrahydro-5H-1 ,4-benzodiazepin-5-one To a solution of Compound A (17g, 29 mmol) in THF (150 mL) was added diethylamine (30 mL, 290 mmol). The solution stirred for 2 h and concentrated. The resulting residue was dissolved in ethyl ether (100 mL) and 1 N aqueous hydrogen chloride (400 mL). A heavy white precipitate formed and was filtered, washed with hexanes/ethyl ether and dried under high vacuum. A portion of the resulting white solid (8.2 g, 24 mmol) with EDC (4.5 g, 24 mmol), HOBt (3.2 g, 24 mmol) and DIEA (12.4 mL, 71 mmol) in DMF (80 mL) was stirred for 16 h and poured into a solution of 10% aq LiCI (200 mL) and ethyl acetate (90 ml). The layers were separated. The organic layer was washed with 4x 40 mL 10%aq LiCI, 4x 1 N aq hydrogen chloride, 2x 50 mL brine and 1x 50 mL water. The solution was dried (Na2S04), filtered and concentrated to give 7.2g (83% overall for the two steps) of Compound B as a white solid. (M+H)+ 329.
C . 7-Bromo-3-[(1 , 1 -dimethylethoxy)methyl]-1 , 2,3,4- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-5H-1 ,4-benzodiazepin-5- one
Example 304 was prepared as a white solid in 40% yield from Compound B as described for Compound D of Example 224 (M+H)+ 409.
Example 305
Figure imgf000260_0001
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenoxymethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
A. 7-Bromo-3-[(1 ,1 -dimethylethoxy)methyl]-1 ,2,3,4- tetrahydro-5H-1 ,4-benzodiazepine Compound B of Example 304 (0.5g, 1.5 mmol) was combined with
10 mL THF and 1M LAH in THF (4 mL, 4 mmol). The solution was refluxed for 16 h. Diethyl ether (40 mL) and 1 N NaOH (40 mL) were added followed by brine and the layers were separated. The organic layer was washed with 1 N aq NaOH, dried (Na2SO4), filtered and concentrated to give 413 mg (88%) of Compound A as a glassy solid. MS (M+H)+ 314.
B. 7-Bromo-3-[(1 ,1-dimethylethoxy)methyl]-4- methanesulfonyl-1 ,2,3,4-tetrahydro-5H-1 ,4-benzodiazepine
Compound B was prepared as a white solid in 71% yield from Compound A as described for Compound C of Example 224. MS (M+H- tBu)+ 337.
C . 7-Bromo-3-(hydroxymethyl)-4-methanesulfonyl-1 ,2,3,4- tetrahydro-5H-1 ,4-benzodiazepine
A solution of Compound B ( 1.1g, 2.8 mmol) in TFA (8 mL) and methylene chloride (8 mL) was stirred for 3 h and concentrated. Trituration with ethyl ether and drying under vacuum afforded 700 mg (74%) of Compound C as a white solid. MS (M+H)+ 337.
D . 7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-
(phenoxymethyl)-l H-1 ,4-benzodiazepine
To a solution of Compound C (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (62 mg, 0.30 mmol). The solution was cooled to -40°C under N2. Triflic anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred under N2 for 1 h at - 40°C. In a separate flask, phenol (100 mg, 1.1 mmol) was added to a solution of sodium hydride (44 mg, 1.1 mmol, 60% dispersion in mineral oil, prewashed with hexanes) in THF (2.5 mL). The solution was stirred for 20 min at ambient temperature under N2 and was added quickly to the trifiate solution. After stirring for 20 minutes, the solution was diluted with methylene chloride (40 mL) and washed with saturated aq sodium bicarbonate solution. The organic layer was dried (Na2SO4), filtered and concentrated to give a solid. This material was chromatographed on flash silica eluting with 1 :1 ethyl acetate:hexanes to afford 30 mg (49%) of Compound D as an off-white solid. MS (M+H)+ 411. E. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
4-(methylsulfonyi)-3-(phenoxymethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride
Example 305 was prepared from Compound D as a white solid in 27% yield as described for Compound D of Example 224. MS (M+H)+ 491.
Example 306
Figure imgf000262_0001
7-Bromo-2,3,4,5-tetrahydro-3-(hydroxymethyl)-1-(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 306 was prepared as an offwhite solid in 12% yield from Compound C of Example 305 as described for Compound D of Example 224. MS (M+H)+ 417.
Example 307
Figure imgf000262_0002
7-Bromo-3-[(1 ,1 -dimethylethoxy)methyl]-2,3,4,5-tetrahydro-1 (1 H-imidazol-4-y lmethyl)-4-(methylsulf onyl)-1 H-1 ,4- benzodiazepine. Example 307 was prepared as an offwhite solid in 23% yield from Compound B of Example 305 as described for Compound D of Example 224.
MS (M+H)+ 472.
Example 308
Figure imgf000263_0001
[7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2- methylpropyl ester, trihydrochloride.
A. 2,3,4,5-Tetrahydro-3-(phenylmethyl)-4-[(1 ,1 - dimethy lethoxy)-carbonyl]-8-amino-1 H-1 ,4-benzodiazepine A solution of 2,3,4,5-tetrahydro-3-(phenylmethyl)-8-amino-1 H-1 ,4- benzodiazepine (described in Compound B of Example 98, 1.0 g, 3.5 mmol) and Boc anhydride (0.77g, 3.5 mmol) were stirred in THF (15 mL) under argon at RT. After 16 hrs, the mixture was concentrated. The residue was triturated with hexane and CHCI3 to afford an olive grey solid. The filtrate was concentrated and triturated with hexane and CHCI3 to afford additional olive green solid. The solids were combined and purified by flash silica gel chromatography (20% then 30% EtOAc in hexane) to afford Compound A (0.542 g, 40%). MS (M+H) 354+.
B. [2,3,4,5-Tetrahydro-3-(phenylmethyl)-4-[(1 ,1 -dimethyl- ethoxy)-carbonyl]-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2- methylpropyl ester
To a solution of Compound A (115 mg, 0.3 mol) in dichloromethane (2 mL) under argon was added DIPEA (0.1 mL, 0.6 mmol) and isobutyl chloroformate dropwise. After 20 min, water (2 mL) and saturated NaHC03 were added and the mixture was extracted with chloroform (15 mL). The organic layer was dried (MgS04) and concentrated in vacuo to afford a solid which was purified by flash silica gel eluting with 20% EtOAc in hexanes to afford Compound B (125 mg, 92%) as a solid. MS (M+H)+ = 454+
C. [7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-[(1 ,1- dimethylethoxy)-carbonyl]-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2-methylpropyl ester To a solution of Compound B (100 mg, 0.22 mmol) in chloroform (2 mL) was added dropwise a solution of tetrabutylammonium tribromide (106 mg, 0.22 mmol) in chloroform (1 mL) over 5 min. After 10 min, the mixture was washed with sodium bisulfate solution (5 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography eluting with 20% EtOAc in hexanes afforded Compound C (110 mg, 94%) as a solid. MS (M+H)+ = 532+
D . [7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-4-[(1 ,1-dimethylethoxy)-carbonyl]-1 H-1 ,4- benzo-diazepin-8-yl]carbamic acid, 2-methylpropyl ester
To a solution of Compound C (100 mg, 0.19 mmol) and 4- formylimidazole (36 mg, 0.3 mmol) in a mixture of dichloromethane (2 mL) and acetic acid (0.6 mL) was added 3A molecular sieves and the mixture was stirred for 15 min. Sodium triacetoxyborohydride (105 mg, 0.5 mmol) was added and the mixture was stirred overnight (18 hr). Another portion of the aldehyde and borohydride reagent (36 mg and 105 mg respectively) were added. After 4 hr., the mixture was filtered through celite and washed with chloroform. The filtrate was concentrated and treated with chloroform and NH4OH (10 mL each). After stirring vigorously for 30 min, the organic layer was separated, dried (MgS04), and concentrated in vacuo to afford Compound D (110 mg, 86%). MS (M+H)+= 612+
E . [7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-yimethyl)- 3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2- methyl-propyl ester, trihydrochloride
To a solution of Compound D (105 mg, 0.17 mmol) in chloroform (1 mL) was added HCl in dioxane (3 mL, 4M solution). After 4 hr the mixture was concentrated. Chloroform (5 mL) was added and the mixture concentrated in vacuo to afford Example 308 as an off-white powder (110 mg, 100%).
MS (M+H)+ = 512
Example 309
Figure imgf000265_0001
[4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2-methyl-propyl ester.
To a solution of Example 308 (18 mg, 0.03 mmol) in DMF (0.2 mL) were added pyridine (0.3 mL), acetic anhydride (0.2 mL), and DMAP (10 mg) and the mixture was stirred for 20 hr. Acetic anhydride (0.1 mL) was added and the mixture was stirred for 4 hr. The mixture was partitioned between chloroform and water (10 mL each). The organic layer was separated and washed with saturated CuS04 (2x10 mL), dried (K2C03) and concentrated. Purification by RP HPLC eluting with 40-90% aqueous methanol containing 0.1% TFA on a C-18 column afforded a solid which was treated with 1 N aqueous HCl (2x10 mL) followed by concentration. The solid was dissolved in water and lyophilized to afford Example 309 as a pale yellow solid (13 mg,
70%).
MS (M+H)+ = 554 Example 310
Figure imgf000266_0001
N-[4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethy l)-3- (phenylmethyl)-l H-1 ,4-benzodiazepin-8- yl]cyclohexanecarboxamide, dihydrochloride.
Example 310 was prepared in 50% yield as a pale yellow solid from Compound C of Example 246 as described for Example 309. MS (M+H)+ = 486
Example 311
Figure imgf000266_0002
[7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-8- yljcarbamic acid, 2-methylpropyl ester.
To a solution of Example 308 (31 mg, 0.05 mmol) in DMF (0.2 mL) at RT were added TEA (0.2 mL), dichloromethane (0.2 mL), and methanesulfonyl chloride (0.024 mL, 0.3 mmol) and the mixture was stirred for 18 hr and partitioned between chloroform and saturated NaHC03 (10 mL each). The organic layer was separated, dried (K2CO3) and concentrated. Purification by RP HPLC eluting with 40-90% aqueous methanol containing 0.1% TFA on a C-18 column afforded a solid which was treated with 1N aqueous HCl (2x10 mL) followed by concentration. The solid was dissolved in water and lyophilized to afford Example 311 as a pale yellow solid (13 mg, 70%). MS (M+H)+ = 590
Example 312
Figure imgf000267_0001
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4- (phenylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitrile, monohydrochloride.
A. (R)-2,3,4,5-Tetrahydro-4-(phenylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile
To a stirred and chilled (0°, ice bath) solution of Compound C of Example 248 (45g, 171.54mmole) containing DIEA (50 ml, 287 mmol) in anhydrous CH2CI2 (1 L) under argon was added dropwise a solution of benzenesulfonyl chloride (30 ml, 235 mmol) in anhydrous CH2CI2 (50ml). After the addition was complete, the mixture was warmed to room temperature and stirred for 4 hr. The solution was diluted with CH2CI2 (500ml), washed with water (2x250ml), 10% KHS04 (750ml), saturated
NaHC03 and brine, which was crystallized from EtOAc-hexane to give 65g (94%) of Compound A as solid. MS (M-H)- 402. 13C-NMR (CDCI3) 40.22, 46.00, 47.23, 61.36, 116.34, 119.55, 120.99, 126.99, 127.11 , 128.10,129.76, 129.40, 131.97, 132.09, 134.03, 136.77, 139.53, 150.77ppm B. (R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(phenylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitrile, monohydrochloride To a stirred solution of Compound A (64.3 g, 159 mmol) and 4- formyiimidazole (15.3 g, 159 mmol) in a mixture of HOAc (glacial, 150 ml) and 1 ,2-dichloroethane (720 ml) under argon was added sodium triacetoxyborohydride (33.8 g, 159 mmol). The mixture was heated to 60°C for 6 hr. Additional 4-formylimidazole (15.3g) and sodium triacety borohydride (33.8g) were added.The addition was repeated three times until HPLC showed 7% unreacted Compound A. The resulting solution was cooled to room temperature. MeOH (250ml) was slowly added and the mixture was stirred for 30 minutes and evaporated. The residue was azeotroped with toluene (2x500ml). The gummy residue was diluted with saturated NaHCO3 solution and stirred. Solid NaHCO3 was added until the foaming ceased. The slurry was extracted with EtOAc (3x1 L). The combined EtOAc extracts were washed with saturated NaHCO3 solution and brine, dried over anhydrous MgS04 and evaporated to give a foam. This was flash-chromatographed on a column of silica gel (E. Merck 230-400 mesh, 1.6 kg) eluting with EtOAc-MeOH (95:5) to give the free base of Example 312. This was dissolved in EtOAc (1.0L), treated with a solution of 1.0N HCl in Et2θ (250 ml), and the mixture stirred for 30 minutes and filtered. The solid was washed with EtOAc (500ml) and E.2O (500ml) and dried in high vacuum at 50° overnight to give 58 g (70%) of Example 312 as a solid. MS (M+ H)+ = 484
Analysis calculated for C27H25N5O2S «0.7 H 0 »1 HCl • 0.05 EtOAc • 0.03 ether.
Calc'd: C, 60.85; H, 5.25; N, 12.99; Cl, 6.57; S, 5.94.
Found: C, 60.85; H, 5.19; N, 13.05; Cl, 6.60; S, 5.95.
Figure imgf000269_0001
7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4H-1 ,4-benzodiazepine-4-acetamide.
A. 7-Bromo-1 ,2,3,5-tetrahydro-3-(phenylmethyl)-4H-1 ,4- benzodiazepine-4-acetamide
A mixture of Compound B of Example 75 (250 mg, 0.74 mmol,), DIEA (0.067 mL, 0.74 mmol) and 2-chloroacetamide (69 mg, 0.74 mmol) in THF (10 mL) was stirred under argon at room temperature for 8 hours. The mixture was partitioned in brine (50 ml) and ethyl acetate (50 mL), the aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (MgSO4) and concentrated to provide Compound A as a clear oil (260 mg, 94 %).
B. 7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-acetamide
Example 313 was prepared as a white solid in 38% yield from Compound A as described in Compound D of Example 1 , with stirring for 18 hours and purification by preparative HPLC. MS (M+ H)+ = 454 Analysis calculated for C22H24NδOBr »0.3 H2O »1.5 TFA.
Calc'd: C, 45.81 ; H, 3.95; N, 10.35; Br, 11.81; F, 16.01. Found: C, 45.43; H, 3.80; N, 9.96; Br, 11.50; F, 15.74.
Figure imgf000270_0001
7-Bromo-4-[(dimethylamino)acetyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine.
A. 7-Bromo-4-(bromoacetyl)-2,3,4,5-tetrahydro-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
Compound A was prepared as a clear oil from Compound B of Example 75 and bromoacetyl bromide as described for Compound A of Example 313, with purification by using flash chromatography (silica, 3:1 hexanes: ethyl acetate)
B. 7-Bromo-4-[(dimethylamino)acetyl]-2,3,4,5-tetrahydro-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
To a solution of Compound A (126 mg, 0.29 mmol) in THF (2 mL) was added dimethyl amine (2 mL, 1 M in THF). The solution was stirred at room temperature in a sealed pressure tube for 7 hours, poured into water and extracted with ethyl acetate. The solution was dried (MgSO4) and concentrated to afford Compound B as an oil (110 mg, 94 %).
C . 7-Bromo-4-[(dimethy lamino)acetyl]-2,3,4,5-tetrahydro-1 ■ (1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine Compound C was prepared as a white solid in 65% yield from
Compound B as described for Compound B of Example 313. MS (M+ H)+ = 483 Analysis calculated for C24H28N5OB I .2 H 0 »2.1 TFA.
Calc'd: C, 45.56; H, 4.41 ; N, 9.42; Br, 10.75; F, 16.10. Found: C, 45.75; H, 4.02; N, 9.19; Br, 11.14; F, 16.08.
Figure imgf000271_0001
(R)-7-Bromo-4-(1 ,2-dioxopropyl)-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 315 was prepared as a white solid in 25% overall yield from Compound B of Example 224 by an EDC/HOBt mediated coupling of pyruvic acid in DMF, with purification by flash chromatography (silica, 4:1 hexanes: ethyl acetate), followed by the method of Compound B of Example
313.
MS (M+ H)+ = 468 Analysis calculated for C-23H23N4θ2Br »0.8 H20 «0.95 TFA.
Calc'd: C, 50.68; H, 4.36; N, 9.49; Br, 13.54; F, 9.18. Found: C, 50.37; H, 4.04; N, 9.23; Br, 14.07; F, 9.55.
Figure imgf000272_0001
(R)-7-Bromo-4-(cyclopropylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
Example 316 was prepared as a white solid in 6% overall yield from Compound B of Example 224 and cyclopropanecarboxylic acid by the two step procedure described in Example 315, with no purification of the intermediate. MS (M+ H)+ = 466 Analysis calculated for C-24H25N4θBr »1.0 H20 »0.8 TFA.
Calc'd: C, 52.59; H, 4.68; N, 9.43; Br, 13.46; F, 9.60. Found: C, 52.62; H, 4.37; N, 9.46; Br, 12.23; F, 9.46.
Figure imgf000272_0002
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(propylsulf onyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. A. (R)-7-Cyano-2,3,4,5-tetrahydro-3-(phenylmethyl)-4- (propylsulf onyl)-1 H-1 ,4-benzodiazepine n-Propylsulfonylchloride (3.4 ml, 34 mmol) was added dropwise to a solution of Compound C of Example 248 (6.0 g, 23 mmol) and DIEA (12 ml, 68 mmol) in methylene chloride (120 ml) at -78°C. The mixture was allowed to warm to room temperature and stirred for 16h, quenched with 10% NaHCOg (50 ml) and extracted with methylene chloride (3X75 ml). The combined organic layers were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by flash chromatography (2/1 hexane/ethyl acetate) to afford Compound A (7.1 g, 85%) as a yellow solid. MS (M+H)+ 370 Analysis calculated for C20H23N3O2S »0.19 H20.
Calc'd: C, 64.42; H, 6.32; N, 11.27. Found: C, 64.43; H, 6.25; N, 11.09.
B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4- benzodiazepine, monohydrochloride
4-Formylimidazole (3.1 g, 33 mmol) was added to a solution of Compound A (6.0 g, 16 mmol) and 3A molecular sieves in 1/1 CH2CI2:acetic acid (80 ml) and the mixture was stirred at 70°C for 1 h. Sodium triacetoxyborohydride (6.9 g, 33 mmol) was added and the mixture was stirred at 70°C for 30 minutes. 4-Formylimidazole (3.1 g, 33 mmol, 2.0 eqiuv) was again added to the mixture and stirring was continued at 70°C for 1h. Sodium triacetoxyborohydride (6.9 g, 33 mmol, 2.0 equiv) was added and the mixture was stirred at 70°C for 30 minutes. Addition of more formylimidazole and hydride was repeated eight times. The mixture was cooled to room temperature, diluted with methylene chloride (200 ml), filtered and the filtrate concentrated under vacuum. The residue was diluted with 25% NH4OH (200 ml). The solution was stirred at room temperature for 10 minutes, extracted with CH2CI2 (2X200 ml) and the combined organic extracts were dried (MgS04), filtered and concentrated. The residue was purified by preparative HPLC (gradient of aq MeOH with 0.1% TFA) and the appropriate fractions were isolated and concentrated under vacuum. The residue was dissolved in CH3OH (20 ml) and 1N HCl (40 ml) and concentrated under vacuum and this procedure was repeated 3X. The residue was dissolved in CH3CN (20 ml) and 1 N HCl (20 ml) and lyophilized to afford Example 317 (6.8 g, 74 %) as a white solid., mp: 140-151 °C. MS (M+H)+450 Analysis calculated for C24H27N5O2S «1.1 HCl -0.59 H20. Calc'd: C, 57.62; H, 5.90; N, 14.00; Cl, 7.79; S, 6.41. Found: C, 57.61 ; H, 5.70; N, 13.97; Cl, 7.62; S, 6.44. [a]D = + 201 ° (c = 1.41 , CH3OH)
Example 318
Figure imgf000274_0001
7-Bromo-2,3,4,5-tetrahydro-1 ,4-bis(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, dihydrochloride.
Example 318 was prepared in 55% yield as a white solid from
Compound B of Example 75 as described for Compound D of Example 1 , using 3 equivalents of formylimidazole and stirring for 2 hours. MS (M+H)+ = 477
Example 319
Figure imgf000275_0001
7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N- dimethyl-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4- sulfonamide, monohydrochloride.
A. 7-Bromo-1 ,2,3,5-tetrahydro-N,N-dimethyl-3- (phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonamide A stirred solution of Compound B of Example 75 (100 mg, 0.32 mmol), N,N-dimethylsulfamoyl chloride (50 mg, 0.35 mmol) and DIPEA (61 uL, 0.35 mmol) in acetonitrile in the presence of a catalytic amount of DMAP was heated at reflux for 18 h. The mixture was partitioned between ethyl acetate and 1 N HCl solution. The organic layer was separated, dried (MgS04) and concentrated. The residue was purified by flash chromatography (1 :2, hexanes:ethyl acetate) to give Compound A as an oil.
B. 7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-yimethyl)- N,N-dimethyl-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4- sulfonamide, monohydrochloride
Example 319 was prepared in 92% yield as a solid from Compound A as described for Compound D of Example 224. MS (M+H)+504 Analysis calculated for C22H26Nδθ2SBr »1.0 HCl *0.5 ether. Calc'd: C, 49.88; H, 5.58; N, 12.12; Br, 13.82; S, 5.55. Found: C, 49.90; H, 5.42; N, 12.13; Br, 13.22; S, 6.44.
Figure imgf000276_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitrile, monohydrochloride.
Example 320 was prepared as a yellow solid from Compound B of Example 75 as described in the following sequence: Compound C of Example 224, Compound A of Example 225, and Compound B of Example 225.
MS (M+H)+422 Analysis calculated for C22H23N5O2S »1.0 HCl «0.2 CH3OH.
Calc'd: C, 57.42; H, 5.38; N, 15.08; Cl, 7.63; S, 6.90. Found: C, 57.12; H, 5.58; N, 11.94; Cl, 7.77; S, 4.95.
Figure imgf000276_0002
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N- dimethyl-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4- carboxamide, monohydrochloride. Example 321 was prepared as a yellow solid from Compound C of Example 248 by the following sequence: Compound A of Example 319, using dimethylcarbamoyl chloride and stirring at 60°C for 2 h and chromatography with 1 :1 hexanes:ethyl acetate; Compound B of Example 225. mp: 147-150°C. MS (M+ H)+ = 415 Analysis calculated for C24H26N6O «0.74 H20 »1.0 HCl.
Calc'd: C, 62.09; H, 6.18; N, 18.10; Cl, 7.61. Found: C, 62.09; H, 6.04; N, 17.86; Cl, 7.91. [a)D20: +244 ° (c = 0.24, MeOH).
Figure imgf000277_0001
N,N-Diethyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carboxamide, monohydrochloride.
A. 2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepine-7-carboxylic acid
A solution of Compound A of Example 225 (200 mg, 0.59 mmol) in ethanol in the presence of 10N NaOH solution (4 mL, 40 mmol) was heated at reflux for 5 h. The mixture was cooled to room temperature, concentrated and aqueous HCl was added to adjust the pH to 3. The mixture was concentrated. The residue was partitioned between 1 N HCl and ethyl acetate. The organic layer was separated, dried over MgS04 and concentrated. The residue was triturated with methanol to give Compound A as a solid (156 mg, 73%). B. N,N-Diethyl-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine-7-carboxamide
To a solution of Compound A (50 mg, 0.14 mmol) in DMF was added diethylamine (50 uL), followed by catalytic amounts of HOBT and DMAP and then EDC (30 mg). The mixture was stirred at room temperature for 2 days and partitioned between ethyl acetate and 1 N HCl solution. The organic layer was separated, washed with sat. NaHC03 solution, dried MgS04, concentrated to give Compound B as an oil.
C . N,N-Diethyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-7-carboxamide, monohydrochloride
Compound C was prepared from Compound B as described for Compound B of Example 225. MS (M+ H)+ = 496.
Example 323
Figure imgf000278_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(1 - phenyl-1 H-tetrazol-5-yl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. 2,3,4,5-Tetrahydro-7-phenyl-4-(1 -phenyl-1 H-tetrazol-5- yl)-1 H-1 ,4-benzodiazepine
A solution of Compound B of Example 12 (100 mg, 0.45 mmol) in DMF (2 mL) was treated with 5-chloro-1-phenyltetrazole (100 mg, 0.55 mmol) in the presence of potassium carbonate (60 mg). The mixture was stirred at 60°C for 18 h and partitioned between ethyl acetate and sat. NH4CI solution. The organic layer was washed with sat. NaHCO3 solution, dried (MgS04), and concentrated. The residue was purified by column chromatography to give Compound A as a white solid (75 mg, 45%), mp: 150-151°C.
B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-
4-(1 -phenyl-1 H-tetrazol-5-yl)-1 H-1 ,4-benzodiazepine, monohydrochloride
Compound B was prepared as a yellow solid from Compound A as described for Compund D of Example 1 , mp 158°C. Analysis calculated for C26H24N8 #0.5 CH3OH »2.5 HCl. Calc'd: C, 57.28; H, 5.17; N, 20.16. Found: C, 57.62; H, 5.12; N, 19.93.
Figure imgf000279_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(2-pyrazinylcarbonyl)-4H-1 ,4-benzodiazepine, monohydrochloride.
Example 324 was prepared as a yellow solid from Compound C of Example 248 and pyrazinecarboxylic acid by the following sequence: Compound B of Example 322, with stirring for 18 hours and purification by flash chromatography (3:2, ethyl acetate: hexanes); Compound B of Example 225.
MS (M+ H)+ = 450.
Analysis calculated for C-26H23N7O «1.2 H2O «1.0 HCM .2 toluene.
Calc'd: C, 66.09; H, 5.78; N, 16.35; Cl, 5.91. Found: C, 65.83; H, 5.45; N, 16.11 ; Cl, 5.96. Example 325
Figure imgf000280_0001
(R)-4-[7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4H-1 ,4-benzodiazepin-4-yl]-4-oxobutanoic acid, methyl ester, monohydrochloride.
A. (R)-4-[7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-4H- 1 ,4-benzodiazepin-4-yl]-4-oxobutanoic acid, methyl ester A stirred solution of Compound B of Example 224 (100 mg, 0.31 mmol) was treated with succinic anhydride (40 mg, 0.40 mmol) in ethyl acetate. The mixture was stirred at room temperature for 18 h and partitioned with 1 N HCl solution. The organic layer was dried (MgSO4), and concentrated to afford Compound A.
B. (R)-4-[7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepin-4-yl]-4- oxobutanoic acid, methyl ester, monohydrochloride
Compound B was prepared as a yellow solid from Compound A as described for Compound B of Example 225. MS (M+ H)+ =511.
Example 326
Figure imgf000281_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(4- morpholinylcarbonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 326 was prepared as a yellow solid from Compound C of Example 248 and morpholinocarbamoyi chloride as described for Example 321.
MS (M+ H)+ = 457.
Analysis calculated for C-26H28 6O2 #0.8 H2O »1.2 HCKJ.2 ether.
Calc'd: C, 60.79; H, 6.24; N, 15.87, Cl, 8.03. Found: C, 60.85; H, 6.02; N, 15.56; Cl, 8.06.
Example 327
Figure imgf000281_0002
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[[2-(1 -pyrrolidinyl)ethyl]sulfonyl]-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 327 was prepared in 46% yield as a light yellow solid from Compound A of Example 250 and pyrrolidine as described for Compound B of Example 250. MS (M+ H)+ = 505. Example 328
Figure imgf000282_0001
(S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-7-phenyl-3-(3-pyridinylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 328 was prepared as an off white solid from L-(3- pyridyl)alanine and Compound B of Example 226 by the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound C of Example 264. MS (M+H)+ 474.
Example 329
Figure imgf000282_0002
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-3-(3- pyridinylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Example 329 was prepared as an off white solid from (R)-2,3,4,5- tetrahydro-7-phenyl-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine (prepared as described in Example 273) and 2-thiophenesulfonyl chloride by the following sequence: Compound C of Example 224; Compound D of Example 224.
MS (M+H)+ 542.
Example 330
Figure imgf000283_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4- (propylsulfonyl)-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-2,3,4,5-Tetrahydro-7-phenyl-4-(propylsulfonyl)-3-(3- pyridinylmethyl)-1 H-1 ,4-benzodiazepine
To a stirred solution of (R)-2,3,4,5-tetrahydro-7-phenyl-3-(3- pyridinylmethyl)-1 H-1 ,4-benzodiazepine (prepared as described in Example 273; 200 mg, 0.63 mmol) and DIEA (0.33 mL, 1.9 mmol) was added propanesulfonyl chloride (0.11 mL, 0.94 mmol) at -60°C under argon. The mixture was kept at 4°C for two days, quenched with aqueous saturated NaHC03 solution (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to afford Compound A as a yellow solid. MS (M+H)+ 422.
B. (R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-4-(propylsulfonyl)-3-(3-pyridinylmethyl)-1 H-1 ,4- benzodiazepine, monohydrochloride Compound B was prepared as a yellow solid from Compound A in 45% yield as described for Compound D of Example 224, with purification by preparative HPLC (gradient of aqueous methonaol with 0.1% TFA). The HCl salt was prepared by adding 1 N HCl in ether to a solution of the TFA salt in ethyl acetate and evaporation. MS: (M+H)+ 502
Example 331
Figure imgf000284_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(2-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 331 was prepared as a yellow solid from D-(2- pyridyl)alanine and Compound B of Example 226 using the following sequence: Compound C of Example 226; Compound D of Example 226, with refluxing for 48 hr; Compound B of Example 264, with purification by preparative HPLC using a gradient of aqueous methanol with 0.1% TFA; Compound C of Example 264. MS (M+H)+ 478.
Example 332
Figure imgf000285_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-7-(2-pyrimidinyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 332 was prepared as a yellow solid from Compound A of Example 231 and 2-stannylpyrimidine as described for Compound B of Example 231 and Compound C of Example 231. MS (M+H)+ 475.
Example 333
Figure imgf000285_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[(trifluoromethyl)sulfonyl]-1 H-1 ,4- benzodiazepine, monohydrochloride. Example 333 was prepared in 44% yield as an off-white solid from Compound B of Example 224 as described for Compound C of Example 224 (using trifluoromethanesulfonyl anhydride instead of methanesulfonyl chloride) and Compound D of Example 224. MS (M+H)+ 528.
Example 334
Figure imgf000286_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-3- (phenylmethyl)-4-(trif luoroacetyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 334 was prepared in 26% yield as a white solid from Compound D of Example 226 by reaction with trifluoroacetic anhydride and DIEA in methylene chloride, followed by the method of Compound C of Example 264, with purification by preparative HPLC (gradient of aqueous methonaol with 0.1% TFA). The HCl salt was prepared by lyophilization twice from 1 N HCl. MS (M+H)+ 491.
Figure imgf000287_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A. (R)-2,3,4,5-Tetrahydro-3-(phenylmethyl)-7-(4-pyridinyl)-
1 H-1 ,4-benzodiazepin-2,5-dione A mixture of Compound A of Example 224 (55.6 mmol, 19.2g), 4- stannylpyridine (111 mmol, 40.9 g) and Pd(PPh3)4 (8.24 mmol, 9.6g) in toluene (2000 mL) was degassed and heated to 110°C for 16 hrs. The reaction was concentrated, diluted with 1 :1 ether/hexanes and filtered. The solid was washed with 500 mL of 1 :1 ether/hexanes to afford 16.7 g of Compound A. The combined filtrate was concentrated and filtered to yield 5.8 g of Compound A (total yield 80%). MS (M+H)+ 344.
B. (R)-2,3,4,5-Tetrahydro-3-(phenylmethyl)-7-(4-pyridinyl)-
1 H-1 ,4-benzodiazepine A suspension of Compound A (16.7, 32 mmol) in THF (250 mL) was treated with BH3-THF (1.0 M in THF). The mixture was heated to reflux for 12 hrs and quenched by the slow addition of 6N HCl (500 mL). THF was removed under reduced pressure, and the remaining solution was made alkaline with the slow addition of concentrated NaOH. The aqueous phase was extracted with 10%IPA-CH2Cl2 (3X300 mL), dried over Na2Sθ4 and concentrated to isolate 9.0 g (90% yield) of Compound B. MS (M+H)+ 316. C . (R)-2,3,4,5-Tetrahydro-4-(methylsulf onyl)-3-
(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine
To a solution of Compound B (28.5 mmol, 9.0 g) in CH2CI2 (200 mL) was added TEA (142.5 mmol, 20 mL) and methanesulfonyl chloride (37.5 mmol, 2.9 mL). The mixture was stirred at rt for 1 hr, poured over 2N NaOH (500 mL) and extracted with 10%IPA-CH2Cl2 (3X250 mL). The combined organic layers were dried over Na2S04, concentrated, and azeotroped with toluene to afford Compound C.
D . (R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methyisulf onyl)-3-(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4- benzodiazepine, dihydrochloride
Crude Compound C was dissolved in 300 mL of 1 :1 AcOH:CH2Cl2 together with NaBH(OAc)3 (123 mmol, 26g) and 4-formylimidazole (123 mmol, 11.8 g) and the mixture heated to 55°C for 3 hrs. The reaction was concentrated, diluted with 2N NaOH (500 mL) and extracted with 10%IPA- CH2CI2 (3X250 mL). The combined organic layers were evaporated and the residue purifed by preparative HPLC (gradient of aq methanol with 0.1% TFA). The TFA salt was converted to the HCl salt with 1 N HCl (2X150 mL) to afford Compound D as a yellow solid (2.9 g, 18% from Compound B). MS (M+H)+ 491.
Example 336-343
Examples 336-343 were prepared from the appropriate sulfonyl chloride and Compound B of Example 335 as described for Compounds C and D of Example 335 (Exs 336-338) or from Compound C of Example 248 as described for Compound A of Example 317 (from 0°C to rt) and Compound D of Example 335 (Exs 339-343).
Example Mass ctrum
336 m/z 542 (M+ H)
337 m z 536 (M+ H)
Figure imgf000289_0001
338 m/z 502 (M+ H)
339 m/z 539
(M+ H)
340 m/z 509 (M+
Figure imgf000290_0001
H)
Figure imgf000291_0001
221970
Example 344
Figure imgf000292_0001
N-[[7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-l H-1 ,4-benzodiazepin-3-yl]methyl]benzamide, dihydrochloride.
A. N-[[7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-1 H- 1 ,4-benzodiazepin-3-yl]methyl]benzamide
To a solution of Compound C of Example 305 (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (62 mg, 0.30 mmol). The solution was cooled to -40°C under N2. Triflic anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred under N2 for 1 h at -40°C. NH3 gas was added via cannula and bubbling continued for 10 min at -40°C. The solution was slowly warmed to rt with continuous bubbling. Ethyl ether (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added and the layers were separated. The organic layer was washed with 1N aqueous HCl. The aqueous layer was made basic with 5N aq. NaOH and the product was extracted with methylene chloride (30 mL). The organic layer was dried (Na2S04) and concentrated to 5 mL. Benzoic acid (26 mg, 0.21 mmol) and EDC (40 mg, 0.21 mmol) were added and the solution stirred for 16 h and concentrated. The residue was chromatographed (flash silica gel, 1 :5-1 :1 ; ethyl acetate:hexane) to give 15 mg (16% for the two steps) of Compound A as a white solid. MS (M+H)+ 439. B. N-[[7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepin-3- yl]methyl]benzamide, dihydrochloride
Compound B was prepared as a white solid in 16% yield as described for Compound D of Example 224. MS (M+H)+ 518.
Example 345
Figure imgf000293_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-N,N- dimethyl-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4- sulfonamide, hydrochloride.
A. (R)-7-Cyano-1 ,2,3,5-tetrahydro-N,N-dimethyl-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonamide
Dimethylsulfamoyl chloride (0.12 mL, 0.16 g, 1.13 mmol) was added to a solution of Compound C of Example 248 (0.2 g, 0.75 mmol) and DIEA (0.19 mL, 1.13 mmol) in acetonitrile (3 mL) at 0°C under argon. After stirring for 16 hr at rt, the reaction was diluted with chloroform (20 mL) and NaHC03 (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 20 mL). The combined organic extracts were washed with NaHC03 (2 x 5 mL), water (1 x 10 mL), and brine (2 x 10 mL), dried over MgS04, filtered and concentrated. The residue was purified on a flash silica column eluting with 30% EtOAc in hexane to afford Compound A as a yellow oil (0.14 g, 51%). MS [M+H]+ = 371 +. B. (R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-N,N-dimethyl-3-(phenylmethyl)-4H-1 ,4- benzodiazepine-4-sulfonamide, hydrochloride
A solution of Compound A (0.068 g, 0.18 mmol), 4-formylimidazole (0.017 g, 0.18 mmol) and AcOH (0.5 mL) in dichloroethane (0.5 mL) and 3A mol. sieves was refluxed for 1 hr. Sodium triacetoxyborohydride (0.038 g, 0.18 mmol) was added. Every day for 6 days additional aldehyde and sodium triacetoxyborohydride were added (1 eq each). After stirring for 6 days, the mixture was diluted with CHCI3 (10 mL), NH4OH (5 mL) and NaHC03 (5 mL), and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCI3 (3 x 30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The product was purified by preparative HPLC (gradient of aqueous methanol with 0.1 % TFA) to afford Compound B as a light yellow solid (40 mg, 50%). MS (M+H)+ = 451
Example 346
Figure imgf000294_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-N,N-dimethyl-1 -[(1 -methyl-1 H- imidazol-5-yl)methyl]-3-(phenylmethyl)-4H-1 ,4-benzodiazepine- 4-sulfonamide, hydrochloride.
A solution of Compound A of Example 345 (0.068 g, 0.18 mmol), 1- methyl-5-formyiimidazole (0.041 g, 0.36 mmol), AcOH (0.2 mL) and 3A mol. sieves in dichloroethane (0.5 mL) was warmed for 2 hr. Sodium triacetoxyborohydride (0.076 g, 0.36 mmol) was added. Additional aldehyde and sodium triacetoxyborohydride (2 eq each) were added at 1.5, 3 and 4.5 hours. After stirring for 2 days, the mixture was diluted with CHCI3 (10 mL), NH4OH (5 mL) and NaHCO3 (5 mL), and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCI3 (3 x 30 mL). The combined organic extracts were washed with NaHCOg and brine (each 2 x 5 mL), dried over MgSO4, filtered and concentrated. The product was purified by reverse phase preparative HPLC (gradient of aq methanol with 0.1% TFA) and converted to its HCl salt to afford Example 246 as a light yellow solid (32 mg, 38%). MS (M+H)+465
Figure imgf000295_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -[(1-methyl-1 H-imidazol-5- yl)methyl]-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, monohydrochloride.
A. (R)-7-Chloro-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-2,5-dione A mixture of chloroisatoic anhydride (25 g, 0.126 mol), D-Phe methyl ester (27.2 g, 0.126 mol) and DMAP (0.4 g) in pyridine (275 mL) was refluxed for 5 days. The mixture was concentrated and dissolved in CH2CI2. The solution was washed with 10% HCl (3 x 100 mL), dried over MgSO4, filtered and concentrated to afford a pink solid (39 g) which was recrystallized 3 times from ether/CH2CI2 to afford Compound A (15.0 g, 40 %). MS [M+H]+ = 301+ - B. (R)-7-Chloro-2,3,4,5-tetrahydro-3-(phenylmethy l)-1 H-1 ,4- benzodiazepine
Borane in THF (1M, 300 mL) was added to Compound A (20 g,
66.5 mmol) in THF (200 mL). The mixture was refluxed for 1 day, cooled in an ice bath, MeOH (115 mL) added slowly, and the mixture concentrated.
The residue was diluted with MeOH (200 mL), 40 mL of 25% HCl was added and the mixture was refluxed for 2 hrs and concentrated to dryness to afford an off white solid which was triturated with ether several times and suspended in water. NaOH (1 N, to pH 11) was added to the suspension and the solid which formed was filtered, washed with ether, and dried in vacuo to afford 7.9 g of Compound B as a light yellow solid. The filtrate was concentrated to afford an additional 10.5 g of Compound B as a light yellow solid (100 %). MS [M+H]+ = 273
C . (R)-7-Chloro-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine
Methanesulfonyl chloride (3.68 mL, 47.6 mmol) was added dropwise as a solution in CH2CI2 (20 mL) to a solution of Compound B (10 g,
36.6 mmol) in CH2CI2 (130 mL) at 0°C under argon. After stirring at rt for 16 hr the reaction was diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with CH2CI2 (2 x 40 mL). The combined organic layers were washed with water (1 x 30 mL), KHS04 (2 x 30 mL), water (1 x 30 mL), NaHCOg (2 x 30 mL), brine (1 x 30 mL), dried over MgS04, filtered and concentrated to afford a golden brown oil. The oil was crystalized from EtOAc/hexanes and the yellow solid triturated with hexane and dried to afford Compound C (10.6 g, 82 %). MS: [M+H]+ = 351
D . (R)-7-Chloro-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H- imidazol-5-yl)methyl]-4-(methylsulfonyl)-3-(phenylmethyl)-1 H- 1 ,4-benzo-diazepine, monohydrochloride
Sodium triacetoxyborohydride (4.83 g, 22.8 mmol) was added to a solution of Compound C (4.0 g, 11.4 mmol), 1-methyl-5-formylimidazole (2.6 g, 22.8 mmol) and AcOH (22 mL) in CH2CI2 (22 mL). After stirring for 2 days, the mixture was diluted with CH2CI2 (30 mL), NH4OH (30 mL) and NaHCO3 (30 L), and stirred for 30 min. The layers were separated, the aqueous layer was extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with NaHC03, water, brine (3 x 30 mL), dried over MgS04, filtered and concentrated to afford 6.0 g of a foamy solid. The product was purified on a flash column eluting with 7/3 EtOAc/hexane (1 L) and 19/1 CHCIj/MeOH (2L) to afford a white foamy solid, which was treated with 1 N HCl in ether (2 x 25 ml). The solid was triturated with ether and dried to afford Compound D as a light yellow solid (3.44 g, 63 %). MS (M+H)+445
Example 348
Figure imgf000297_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 348 was prepared as a light yellow solid in 70% yield from Compound C of Example 247 as described for Compound D of Example 247, using 4-formylimidazole and with refluxing for 1 hour and stirring at rt for 16 hours. MS (M+ H)+ = 431
Example 349
Figure imgf000298_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5- yl)methyl]-4-(phenylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, monohydrochloride.
Example 249 was prepared as a light yellow solid from Compound B of Example 247 by the following sequence: Compound C of Example 247, with benzenesulfonyl chloride, with stirring at rt for 3 hours and chromatography on silica with 7/3 hexanes/EtOAc (57 %); Compound D of Example 247, with stirring at rt for 12 hours and with stirring for 2 days following addition of another equivalent of hydride and aldehyde, and with purification by reverse phase HPLC (gradient of aqueous methanol with 0.1% TFA; 52%). MS (M+ H)+ = 507.
Figure imgf000299_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, tetrahydrochloride.
A. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(pyridin-3-ylmethyl)- 1 H-1 ,4-benzodiazepine Borane-THF (1 M, 168 ml, 0.168 mmol) was added dropwise to a solution of (R)-7-bromo-2,3,4,5-tetrahydro-3-(pyridin-3-ylmethyl)-1H-1 ,4- benzodiazepin-2,5-dione (prepared from 5-bromoisotoic anhydride and D-3- pyridylalanine methyl ester hydrochloride as described for Compound C of Example 226; 11.2 gm, 32.4 mmol) in THF (50 ml) at 0°C. When effervescence ceased, the mixture was heated to reflux for 4h, cooled to 0°C and an additional equivalent of 1M borane-THF (32.4 ml, 32.4 mmol) was added. The mixture was refluxed for 2h, cooled to 0°C and quenched by dropwise addition of 6N HCl (125 ml) followed by refluxing the mixture for 1h. The reaction was cooled to rt and concentrated under vacuum. The solid was dissolved in water (100 ml) and the solution was extracted with
Et20 (3X100 ml). The aqueous layer was cooled to 0°C and sodium hydroxide (50%) was added until the solution became basic. The basic solution was extracted with 9/1 C^CL iPrOH (3X200 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to afford Compound A (8.0 gm, 80%). MS (M+H)+ 318, 320.
B. (R)-7-Cyano-2,3,4,5-tetrahydro-3-(pyridin-3-ylmethyl)- 1 H-1 ,4-benzodiazepine
Copper cyanide (2.6 gm, 29 mmol) was added to a nitrogen purged solution of Compound A (8.3 gm, 26 mmol) in NMP (41.5 ml) at room temperature. The mixture was heated to 195°C for 3h, cooled to room temperature and quenched with cone NH4OH (100 ml). Water was added and the mixture was extracted with 9/1 CH2CL; iPrOH (3X200 ml). The combined organic extracts were concentrated under vacuum. The residue was dissolved in 6N HCl (200 ml) and extracted with ethyl acetate (4X200 ml). The aqueous solution was cooled to 0°C, made basic with concentrated ammonium hydroxide and extracted with 9/1 CH2C iPrOH (3X200 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum. The residue was flash chromatographed (step gradient, ethyl acetate, 19/1 CHgCL/iPrOH, 4/1/0.2 CH2CI2 / MeOH / triethylamine). The appropriate fractions were concentrated under vacuum to afford Compound B (4.1 g, 60%) as a brown solid. MS (M+H)+ 265
C . (R)-7-Cyano-2,3,4,5-tetrahydro-3-(pyridin-3-ylmethyl)-4- (methylsulfonyl)-l H-1 ,4-benzodiazepine
Methylsulfonylchloride (0.031 ml, 0.39 mmol) was added dropwise to a solution of Compound B (0.070 g, 0.27 mmol) and DIEA (0.14 ml, 0.80 mmol) in methylene chloride (2 ml) at -78°C. The mixture was allowed to warm slowly to room temperature and was stirred at rt for 16h. The mixture was quenched with 10% NaHCO3 (10 ml) and the solution was extracted with methylene chloride (3X10 ml). The combined organic layers were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19/1 methylene chloride/iPrOH) to afford Compound C (0.064 g, 85%) as a solid. MS (M+H)+ 343
D . (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4- benzodiazepine, tetrahydrochloride
4-Formylimidazole (0.062 g, 0.64 mmol) was added to a solution of Compound C (0.55 g, 0.16 mmol) and 3A molecular sieves in 1/1 DCE: acetic acid (2 ml) and the mixture was stirred at 70°C for 1h. Sodium triacetoxyborohydride (0.034 g, 0.32 mmol) was added and the mixture was stirred at 70°C for 30 minutes. 4-Formylimidazole (0.032 g, 0.32 mmol) was added and the mixture was stirred at 70°C for 1h. Sodium triacetoxyborohydride (0.34 g, 0.32 mmol) was added and the mixture was stirred at 70°C for 30 minutes. The latter two steps were repeated six times. The mixture was cooled to rt, diluted with methylene chloride (30 ml), filtered and the filtrate concentrated under vacuum. The residue was diluted with 25% NH4OH (50 ml) and the solution was extracted with CH2CI2 (2X200 ml). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by preparative HPLC (gradient of aq MeOH with 0.1 % TFA) and the appropriate fractions were concentrated under vacuum. The residue was evaporated from CH3OH (1 ml) and 1 N HCl (1 ml) 4X. The residue was dissolved in CH3CN (1 ml) and 1 N HCl (1 ml) and lyophilized to afford Compound D (0.040 g, 50 %) as a solid, mp: decomp above 180°C MS: (M+H)+423 [a]D = + 89° (c = 0.39, CH3OH) Analysis calculated for C21 H22N6 O2S »1.4 H20 «4 HCl. Calc'd: C, 42.44; H, 4.90; N, 14.14. Found: C, 42.44; H, 4.66; N, 14.01.
Example 351
Figure imgf000302_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-2-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
The product was prepared as an offwhite solid in 54% yield from Compound C of Example 224 and 2-formyl imidazole as described for Compound D of Example 1. MS (M+ H)+ = 476.
Example 352
Figure imgf000302_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 methyl-1 H-imidazol-4-yl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trihydrochloride. Example 352 was prepared as an offwhite solid in 54% yield from Compound B of Example 224 and 1-methylimidazole-4-sulfonyl chloride as described for Compounds C and D of Example 224. MS (M+ H)+ = 542.
Example 353
Figure imgf000303_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -(1 -methyl-imidazol-5- ylmethyl)-4-[(2-morpholin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride.
A. (R)-7-Chloro-2,3,4,5-tetrahydro-4-(ethenylsulfonyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
To a solution of 4.4g (16.1 mmol) of Compound B of Example 347 in 75 ml of methylene chloride, at -78 °C and under argon, was added dropwise approximately one-half of a solution of 2.5 ml (24.2 mmol) of 2- chlorosulfonyl chloride in 15 ml of methylene chloride. Then was added rapidly dropwise 5 ml of DIPEA, followed by the remaining sulfonyl chloride solution and an additional 2.4 ml of DIPEA (total 7.4 ml, 40.3 mmol). The resulting pale yellow solution was stirred at -78°C for 0.5 hr, allowed to warm to rt and reduced to one-half volume. The solution of crude Compound A was used directly.
B. (R)-7-Chloro-2,3,4,5-tetrahydro-4-[(2-morpholin-4-yl- ethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
Morpholine (15 ml) was added rapidly dropwise to the solution of Compound A and stirring was continued overnight at rt. The reaction was washed with water and brine, dried (MgS04) and the solvent removed to give an orange oil residue, which was subjected to flash chromatography on a silica gel (5% ethyl acetate-hexane) to afford 3.9 g (54%) of Compound B as a solid white foam.
C . (R)-7-Chloro-2,3,4,5-tetrahydro-1 -(1 -methyl-imidazol-5- ylmethyl)-4-[(2-morpholin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride.
To a solution of 3.9 g (8.7 mmol) of Compound B in 40 ml of methylene chloride and 4 ml of acetic acid, at rt and under argon, was added 3.8 g (34 mmol) of 1-methyl-5-imidazolecarboxaldehyde. After stirring 0.5 hr, 1.9 g (9 mmol) of sodium triacetoxyborohydride was added and the solution heated at 40°C. Additional 1.9 g portions of hydride were added at 1 and 2.5 hours. At 4 hr an additional 1.0 g of aldehyde and 1.9 g of hydride were added and stirring was continued overnight at rt. The reaction was evaporated to dryness and the residue diluted with ethyl acetate and sat
NaHCO3. Additional solid NaHCO3 was added in portions until the aqueous layer remained alkaline. The organic layer was separated and the aqueous layer extracted twice more with ethyl acetate. The combined organic fractions were washed with brine, dried (MgS04) and the solvent removed to give a viscous oil residue, which was purified by flash chromatography on silica (10% methanol-chloroform) followed by preparative HPLC (gradient of aqueous methanol with 0.1%TFA) to afford 3.2 g of the free base as a solid white foam. To a solution of the free amine in ethyl acetate was added excess 1 M HCI-ether and the resulting white precipitate collected by filtration to afford 3.2 g (63%) of Compound C as a white powder. MS: (M+H)+544
Analysis calculated for C27H34N5O3SCI»2HCI*H20. Calc'd: C, 51.07; H, 6.03: N, 11.03. Found: C, 50.76: H, 5.94: N, 11.13.
Example 354
Figure imgf000305_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2- morpholin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A mixture of Compound B of Example 353 (0.10 g, 0.22 mmol), 4- formylimidazole (0.042 g, 0.32 mmol), 3A sieves and AcOH (0.3 mL) was refluxed in dichloroethane (0.3 mL) under argon for 2 hours. Sodium triacetoxyborohydride (0.07 g, 0.32 mmol) was added and the mixture was refluxed for 1 hour, stirred at rt for 16 hr, and diluted with CHCI3, NH4OH, and NaHCOg (each 5 mL). The layers were separated and the aqueous layer was extracted with CHCI3 (2 x 20 mL). The combined organic extracts were washed with water and brine (each 2 x 5 mL), dried over MgS04, filtered and concentrated. The residue was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA). The appropriate fractions were concentrated and the residue evaporated from MeOH (1 mL) and 1N HCl (1 mL) 3 times. The residue was dissolved in water and lyophilized to afford Example 354 (0.034 g, 29%) as a solid. MS (M-H)" = 529.
Example 355
Figure imgf000306_0001
(R)-7-Chloro-4-[(dimethylamino)sulfonyl]-1 -[(1-methyl-1 H- imidazol-5-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-7-Chloro-4-[(dimethylamino)sulfonyl]-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
Dimethylsulfamoyl chloride (0.058 mL, 0.54 mmol) was added dropwise to a solution of Compound B of Example 347 (0.1 g, 0.36 mmol) and DIEA (0.095 mL, 0.54 mmol) in CH3CN (2 mL) at 0°C under argon. The mixture was slowly warmed to rt over 16 hr and diluted with NaHCOg (3 mL) and CHCIg (10 mL). The layers were separated and the aqueous layer was extracted with CHCI3 (2 x 30 mL). The combined organic layer was washed with NaHC03 (1 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL), dried over MgS04, filtered and concentrated to afford an orange oil, which was purified on a silica gel flash column (30 % EtOAc/hexane) to afford Compound A as a clear oil 2 (0.44 g, 32 %). MS (M+H)+ 380.
B. (R)-7-Chloro-4-[(dimethylamino)sulfonyl]-1-[(1 -methyl- 1 H-imidazol-5-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, monohydrochloride Compound B was prepared as a white solid in 52% yield from
Compound A as described for Compound C of Example 353, with refluxing for 4 hours and with purification only by preparative HPLC. MS (M+H)+474. Example 356
Figure imgf000307_0001
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -(1 -methyl-imidazol-5- ylmethyl)-4-[(4-methyl-piperidin-4-yl-ethyl)sulfonyl]-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, dihydrochloride.
Example 356 was prepared as a light yellow solid in 28% yield from Compound A of Example 353 and 1 -methylpiperazine as described for Compound B of Example 353, with chromatography using 20% acetone in hexane followed by 10% methanol in CHCI3 and Compound C of Example 353, with purification by preparative HPLC only. MS: [M+H]+ = 557.
Example 357
Figure imgf000307_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 -methyl-imidazol-5-ylmethyl)- 4-[(4-methyl-piperidin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)-1 H- 1 ,4-benzodiazepine, dihydrochloride.
Example 357 was prepared as a white solid in 23% yield from Compound B of Example 224 and 1 -methylpiperazine as described by the following sequence: Compound A of Example 353; Compound B of Example 353, with chromatography using 9/1 CHCI3/ MeOH; Compound C of Example
353, with purification by preparative HPLC only.
MS: [M+H]+ =601.
Example 358
Figure imgf000308_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, isopropyl ester, hydrochloride.
Example 358 was prepared as a light yellow solid in 42% yield from Compound C of Example 248 by the following sequence: Compound E of Example 248, using a toluene solution of isopropyl chloroformate with chromatography using 40% hexane in EtOAc and with the free base carried on; Example 354. MS: [M+H]+ = 430.
Example 359
Figure imgf000308_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-4-[[2-(1 H-imidazol-1- yl)ethyl]sulfonyl]-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride. Example 359 was prepared as a light yellow solid in 21% yield from Compound B of Example 224 as described in the following sequence: Compound A of Example 353; Compound B of Example 353, using sodium imidazolate, 2:1 THF:IPA as solvent, and chromatography using 10% EtOAc in CHCI3 followed by EtOAc; Compound C of Example 353, with addition of aldehyde and hydride every day for 8 days, and no purification. MS: [M+H]+ = 557.
Example 360
Figure imgf000309_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (propylsulfonyl)-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 360 was prepared as a white solid in 15% yield from n- propanesulfonylchloride and Compound B of Example 350 as described for Compounds C and D of Example 350. MS: (M+H)+451
Analysis calculated for C23H26N6O2S • 2.6 HCl • 2.02 H20. Calc'd: C, 47.50; H, 5.65; N, 14.45. Found: C, 47.50; H, 5.51 ; N, 14.10.
Example 361
Figure imgf000310_0001
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-1 H-1 ,4-benzodiazepin-5-one, hydrochloride.
A. 7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-1 ,4- benzodiazepin-5-one
To a suspension of 0.5 g (1.45 mmol) of Compound A of Example 75 in 5 ml of THF, at rt and under argon, was added 3 ml (3 mmol) of 1 M borane in THF. Stirring was continued overnight, after which an additional 2 ml (2 mmol) of 1 M borane in THF was added and stirring continued an additional 8 hr. After hydrolysis of excess borane by the dropwise addition of methanol, the reaction was evaporated to dryness and the residue dissolved in 0.5 ml each of methanol and cone HCl. The resulting solution was heated at reflux for 2 hr, cooled to rt and evaporated to dryness. The residue was evaporated from methanol an additional three times. The crude product was dissolved in ethyl acetate and the solution washed with brine, dried, and the solvent removed to afford a viscous yellow oil, which was subjected to flash chromatography on silica gel (50% ethyl acetate/hexane) to give 205 mg (43%) of Compound A as a white solid.
B. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-5-one, hydrochloride To a suspension of 205 mg (0.62 mmole) of Compound A in 10 ml of methylene chloride and 1 ml of acetic acid was added 120 mg (1.25 mmol) of 4-formylimidazole. The solution was stirred 1 hr, 197 mg (0.93 mmol) of sodium triacetoxyborohydride was added and stirring continued overnight. An additional 60 mg of 4-formylimidazole and 100 mg of sodium triacetoxy- borohydride were added and stirring continued an additional 4 hr. The reaction was evaporated to dryness. The residue was diluted with methylene chloride and the solution washed with sat. NaHCθ3 and brine, dried (MgSθ4), and the solvent removed to afford a pale yellow solid foam residue, which was subjected to preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Concentration of the appopriate fractions afforded a clear oil residue which was converted to the HCl salt by treatment with HCI-MeOH to give 187 mg (60%) of Compound B as a near white solid. MS: (M+H)+ 411.
Analysis calculated for C2oHιgN4θBr • 1.5 HCl • 0.5 C2HιoO. Calc'd: C; 52.53, H; 5.11 , N; 11.14. Found: C; 52.82, H; 4.71 , N; 11.52.
Example 362
Figure imgf000311_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-1 -ylacetyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
A. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(chloroacety l)-4-
(methyisulfonyl)-3-(phenyimethyl)-1 H-1 ,4-benzodiazepine To a mixture of Compound C of Example 224 (2.0 g, 5.06 mmol) and DIEA (4.4 mL, 25 mmol) in dichloromethane (100 mL) in an ice bath under argon, was added chloroacetyl chloride (2.0 mL, 25.3 mmol). The mixture was stirred for 30 min, poured into aqueous sodium hydroxide (200 mL, 1 N) and extracted with dichloromethane (2 x 100 mL). The organic layers were combined, washed with brine (200 mL), and water (200 mL), dried (MgS04) and concentrated to an oil, which was purified by flash chromatography (60 g silica, 3:1 hexane : ethylacetate) to provide Compound A (760 mg, 1.62 mmol, 33 %) as a colorless oil. B. (R)-7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-1- ylacetyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate
A mixture of Compound A (300 mg, 0.64 mm), potassium carbonate (177 mg, 1.28 mmol) and imidazole (87 mg, 1.28) was stirred for 48 hours. The mixture was poured into aqueous hydrochloric acid (200 mL, 1 N) and ethyl acetate (200 mL), separated, and the aqueous adjusted to pH 11 with solid sodium hydroxide. The basic aqueous solution was extracted with ethyl acetate (200 mL) and the organic extracts were combined and dried (Na2S04), and concentrated in vacuo to a semi-solid which was purified by preparative HPLC (aqueous methanol gradient containing 0.1 % trifluoroacetic acid, C-18 column) and lyophilized to provide Compound B as a white solid (100 mg, 32 %). MS: (M+H)+504
Example 363
Figure imgf000312_0001
1 ,2,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-2-(2-phenylethyl)- 3H-1 ,4-benzodiazepin-3-one.
A. 1 ,2,4,5-Tetrahydro-2-(2-phenylethyl)-3H-1 ,4- benzodiazepin-3-one
To a stirred solution of N-Boc-(2-amino)-benzylamirfe (1.0 g, 4.5 mmol) and ethyl 2-oxo-4-phenylbutyrate (1.0 mL, 5.3 mmol) in dichloroethane (20 mL) and acetic acid (1.0 mL) was added NaBH(OAc)3 in one portion at room temperature under argon. The mixture was allowed to stir for 18 h.TFA (4 mL) was added, and the mixture was heated at 60°C under argon for 2 h. The solvent was removed and the residue was dissolved in methanol (15 mL). The solution was cooled to 0°C, and 10 N NaOH solution was added to pH 11. The solution was allowed to stir at rt for 18 h. The solvent was removed and the residue was partitioned between ethyl acetate and saturated NaHC03 solution. The organic layer was separated, dried over MgS04, and concentrated in vacuo. The residue was crystallized from MeOH to give Compound A (480 mg, 40%) as a white solid, mp: 147-148°C.
B. 1 ,2,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-2-(2- phenylethyl)-3H-1 ,4-benzodiazepin-3-one Compound B was prepared as a white solid from Compound A as described for Compound D of Example 1. MS: (M+H)+ 347.
Example 364
Figure imgf000313_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-2-(2- phenylethyl)-1 H-1 ,4-benzodiazepine
To a stirred suspension of lithium aluminium hydride (160 mg) in glyme was added a solution of the free base of Example 363 (150 mg) in glyme at room temperature under argon. The mixture was allowed to stir at room temperature for 18 h, quenched by addition of ethyl acetate (20 mL) followed by ammonium hydroxide (0.5 mL), stirred for 2 h and filtered. The filtrate was concentrated in vacuo to give Compound A as an oil. B. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride
To a stirred solution of Compound A (50 mg) in methylene chloride (5 mL) in the presence of solid K2CO3 was added 100 uL of methanesulfonyl chloride at room temperature. The solution was stirred for 30 min, diluted with 10 mL of methanol followed by 1 mL of 10N NaOH solution, stirred for 2 h and concentrated. The residue was partitioned between ethyl acetate and saturated NH4CI solution. The organic layer was separated, dried over MgS04, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/methanol/NH4OH; 10:1 :0.1) to give an oil, which was converted to its HCl salt as described for Compound D of Example 1. MS: (M+H) 411.
Example 365
Figure imgf000315_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-7-phenyl-3-(4-pyridinylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 365 was prepared as a light yellow solid in 99% yield from Compound B of Example 226 and D-(4-pyridyl)alanine by the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound D of Example 264. MS (M+H)+ 474.
Example 366
Figure imgf000315_0002
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-2-ylmethyl)-4-(phenyl- sulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitrile, hydrochloride. Example 366 was prepared as a yellow solid in 95% yield from Compound A of Example 312 and 2-formyl imidazole as described for Compound D of Example 1. MS (M+H)+ = 484.1. Analysis calculated for C27H25N5O2S »0.6 H20 • 1.1 HCl.
Calc'd: C, 60.67; H, 5.15; N, 13.10; S, 5.99; Cl, 7.29. Found: C, 60.34; H, 5.16; N, 12.81; S, 5.74; Cl, 7.46.
Figure imgf000316_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N- dimethyl-3-(3-pyridinylmethyl)-4H-1 ,4-benzodiazepine-4- carboxamide, dihydrochloride.
Example 367 was prepared as a solid in 2% yield from N,N- dimethylcarbamoyl chloride and Compound B of Example 350 as described in the following sequence: Compound C of Example 350, with extraction using 10% isopropanol/methylene chloride; Compound D of Example 350, with extraction using 10% isopropanol/methylene chloride and lyophilization from 1 N HCI/methanol. HRMS: (M+H)+ Calc : 416.2198; Found: 416.2211.
Figure imgf000317_0001
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N- dimethyl-3-(3-pyridinylmethyl)-4H-1 ,4-benzodiazepine-4- sulfonamide, dihydrochloride.
Example 368 was prepared as a solid in 1% yield from N,N- dimethylsulfamoyl chloride and Compound B of Example 350 as described in Example 367. HRMS: (M+H)+ Calc : 452.1868; Found: 452.1860.
Example 369
Figure imgf000317_0002
4-[(4-Fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1-[(1 -methyl-1 H- imidazol-5-yl)-3-(phenylmethyl)-1 H-thieno[2,3-e]-1 ,4-diazepine, monohydrochloride.
A. 2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-thieno[2,3-e]-
1 ,4-diazepin-2,5-dione
A stirred solution of D,L-N-(2-cyano-1-oxoethyl)-phenylaianine, methyl ester (5.0 g, 20 mmol), dithianediol (1.6 g, 10.5 mmol), piperidine (2.0 mL, 20.2 mmol) and TEA (2.8 mL, 20.2 mmol) in ethanol (30 mL) was heated at reflux for 3 h and evaporated. The residue was evaporated from toluene three times. The dry residue was dissolved in pyridine, and pyridinium chloride (2.0 g) was added. The solution was heated under argon at 130°C for 3 days and evaporated. The residue was dissolved in methylene chloride and the solution was washed with 1 N HCl solution (2 x 100 mL). The organic layer was dried and concentrated in vacuo. The residue was triturated with ether to give Compound A as a brown solid (2.0 g, 40%), mp 268-270 °C.
B. 2,3,4,5-tetrahydro-3-(phenylmethyl)-1 H-thieno[2,3-e]- 1 ,4-diazepine
To a stirred suspension of lithium aluminum hydride (400 mg) in glyme was added Compound A (500 mg, 2.05 mmol) in small portions at room temperature under argon. The resultant suspension was heated at reflux for 3 days, cooled to 0°C, and the excess LAH was destroyed by slow addition of ethyl acetate. NH4OH solution (1 mL) was added and the resultant suspension was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was triturated in ether to give Compound B as a brown solid (220 mg), mp 139-141 °C. MS: (M+H)+ 245.
C . 4-[(4-Fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-3- (phenylmethyl)-l H-thieno[2,3-e]-1 ,4-diazepine To a stirred solution of Compound B (150 mg, 0.6 mmol) in methylene chloride with saturated NaHCO3 solution was added 4- fluorobenzenesulfonyl chloride (300 mg, 1.55 mmol). The mixture was stirred at room temperature for 18 h and diluted with methanol. 10N NaOH was added and the mixture was stirred for 2 h. Concentrated NH40H was added and the mixture was stirred for 18 h and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated NaHC03. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography (1 :4, ethyl acetate and hexanes) to give Compound C as an oil (120 mg, 50%). D . 4-[(4-Fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -[(1- methyl-1 H-imidazol-5-yl)-3-(phenylmethyl)-1 H-thieno[2,3-e]-1 ,4- diazepine, monohydrochloride
Compound D was prepared as a solid in 48% yield from Compound C and 1-methyl-5-formylimidazole as described for Compound D of Example 224. MS (M+H)+ 497.
Figure imgf000319_0001
(R)-2,3,4,5-Tetrahydro-1 -(1 -(4-cyanophenylmethyl)-imidazol-5- ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-7-carbonitrile, hydrochloride.
A. (R)-2,3,4,5-Tetrahydro-1-(1 -(triphenylmethyl)-imidazol-4- ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-7-carbonitrile
To a solution of 1.2 g (2.85 mmol) of the free base of Example 225 in 20 ml of acetonitrile, at rt and under argon, was added 1.2 ml (8.55 mmol) of TEA, followed by 1.2 g (4.3 mmol) of triphenylmethyl chloride. Stirring was continued overnight. The resulting cloudy solution was evaporated to dryness and the residue subjected to flash chromatography on a 100 cc column of silica gel (50% ethyl acetate-hexane) to afford 1.2 g (64%) of Cmpd A as a viscous white foam. B. (R)-2,3,4,5-Tetrahydro-1 -(1 -(4-cyanophenylmethyl)- imidazol-5-ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H- 1 ,4-benzodiazepine-7-carbonitrile, hydrochloride
A solution of 200 mg (0.3 mmol) of Compound A and 59 mg (0.3 mmol) of 4-cyanobenzyl bromide in 0.5 ml of DMF was heated at 100°C, under argon, for 10 hr. The reaction was diluted with methylene chloride and 0.1 ml of triethylsilane was added, followed by 0.5 ml of TFA. The mixture was stirred 1 hour and evaporated to give a yellow viscous oil residue which was combined with material obtained form a similar reaction and subjected to silica flash chromatography (2% methanol-chloroform) to afford 76 mg of viscous tan foam. A second silica flash chromatography (1% methanol-chloroform, then 3% methanol-chloroform) afforded 53 mg of the free base of Compound B as a solid white foam. To a solution of 50 mg of free base in ethyl acetate was added 90 μl 1 M HCl in ether. The resulting white precipitate was collected by filtration and dried to afford 43 mg (0.07 mmole) of Compound B as a white solid. Analysis calculated for C20H28N6N2S»HCI«H20. Calc'd: C, 60.96; H, 5.29: N, 14.22. Found: C, 61.11 ; H, 5.10; N, 14.07. MS (M+ H)+ = 537.
Example 371
Figure imgf000320_0001
(R)-2,3,4,5-Tetrahydro-1-(1-(4-cyanophenylmethyl)-imidazol-4- ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-7-carbonitrile, hydrochloride. A. (R)-2,3,4,5-Tetrahydro-1 -(1 -((1 ,1 -dimethyl)- ethoxycarbonyl)-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3- (phenyl ethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile
To a solution of 250 mg (0.53 mmol) of the free base of Example 225 and 0.6 mg (0.005 mmol) of DMAP in 2 ml of methylene chloride, at rt and under argon, was added a solution of 144 mg (0.66 mmol) of BOC anhydride in 2 ml of methylene chloride. Stirring was continued for 1 hr. The reaction, without workup, was subjected to flash chromatography on a 50 cc column of silica gel (45% ethyl acetate-hexane) to afford 307 mg (approx 100%) of Compound A as a solid white foam.
B. (R)-2,3,4,5-Tetrahydro-1 -(1 -(4-cyanophenylmethyl)- imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-(phenylmethyl)-1 H- 1 ,4-benzodiazepine-7-carbonitrile, hydrochloride A solution of 60 mg (0.115 mmol) of Compound A and 23 mg
(0.115 mmol) of 4-cyanobenzyl bromide in 1 ml of DMF was heated at 100°C, under argon, for 10 hr and evaporated. The residue was diluted with methylene chloride and sat NaHCO3 and stirred for 0.5 hr. The organic layer was separated, dried (MgS04) and the solvent removed to yield a clear colorless glass residue. The crude product was subjected to flash chromatography on a 25 cc column of silca gel (1% methanol-chloroform, then 3% methanol chloroform) to afford 6 mg of the free base of Compound B as a solid white foam. To this material in minimal ethyl acetate was added 100 μl 1 M HCl in ether. The resulting white precipitate was collected by filtration and dried to afford 4.5 mg (7%) of Compound B as a white solid. MS: (M+H)+537
Example 372
Figure imgf000322_0001
(R)-4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-3- (phenylmethyl)-l H-1 ,4-benzodiazepine Benzoyl chloride (2.2 mL, 1.9 mmol) was added to a solution of
Compound C of Example 248 and DIEA (0.32 mL, 1.99 mmol) in dichloromethane (3 mL) at 0°C under argon. The solution was slowly warmed to rt. At 15 and 30 hr, 0.5 equivalents of benzoyl chloride and DIEA were added. After stirring for 2 days, the mixture was diluted with chloroform (20 mL) and NaHCO3 (5 mL). The layers were separated, the aqueous layer was extracted with chloroform (2 x 15 mL). The combined organic extracts were washed with NaHCO3 (2 x 5 mL), water (1 x 10 mL) and brine (2 x 10 mL), dried over MgS04, filtered and concentrated. The residue was purified on a flash column eluting with 20% and 30% EtOAc in hexane to afford Compound A as a yellow oil 2 (0.21 g, 77 %). MS (M+H)+ 368.
B. (R)-4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride A mixture of Compound A (0.1 g, 0.27 mmol), 4-formylimidazole
(0.039 g, 0.40 mmol), AcOH (0.3 mL) in toluene (1 mL) and 3A sieves was refluxed for 15 hrs. Sodium triacetoxyborohydride (0.086 g, 0.4 mmol) was added and the mixture was refluxed for 8 hr, cooled to rt and stirred 15 hours. An additional equivalent of aldehyde was added, the solution was stirred 30 minutes, and an additional equivalent of hydride was added and the solution was stirred 16 hours. An additional equivalent of aldehyde and hydride was added as above, and the mixture was stirred 4 hours, diluted with CHCIg (10 mL), NH4OH (5 mL) and NaHCO3 (5 mL), and stirred for 10 min. The layers were separated and the aqueous layer was extracted with CHCIg (3 x 30 mL). The combined organic extracts were washed with
NaHCOg, water, and brine ( each 2 x 10 mL) dried over MgS04, filtered and concentrated. The product was purified by preparative HPLC, (gradient of aqueous MeOH with 0.1 % TFA). The appropriate fractions were concentrated under vacuum. The residue was evaporated from MeOH (1 mL) and 1 N HCl (1 mL) three times. The residue was dissolved in water and lyophilized to afford Compound B as a light yellow solid (36 mg, 30 %). MS (M+ H)+ = 448.
Figure imgf000323_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5- yl)methyi]-3-(pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 373 was prepared as a solid in 13% yield from Compound B of Example 350 as described for Compound C of Example 350 and Compound D of Example 350, using 1-methyl-5-formylimidazole. MS: (M+H)+437 Analysis calculated for C22H24N6O2S • 2 HCl • 2.1 H20. Calc'd: C, 48.28; H, 5.56; N, 15.36. Found: C, 48.28; H, 5.42; N, 15.45.
Figure imgf000324_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1-[(1 -methyl-1 H-imidazol-5- yl)methyl]-3-(pyridin-3-ylmethyl)-4-(propylsulfonyl)-1 H-1 ,4- benzodiazepine, trihydrochloride.
Example 374 was prepared as a solid in 11% yield from propanesulfonyl chloride as described for Example 373. MS: (M+H)+465
Analysis calculated for C24H28N6O2S • 3 HCl • 0.26 H2O. Calc'd: C,49.82; H, 5.49; N, 14.52. Found: C, 49.81 ; H, 5.37; N, 14.58.
Example 375
Figure imgf000324_0002
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -[(1 H-imidazol-4-yl)methyl]-3- (pyridin-3-ylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. Example 375 was prepared as a solid in 2% yield from Compound B of Example 350 as described for Compound C of Example 350 using benzenesulfonyl chloride, and Compound D of Example 350. MS: (M+H)+485
Example 376
Figure imgf000325_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine.
A. 2,3,4,5-Tetrahydro-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a mixture of Compound B of Example 75 (200 mg, 0.63 mmol) in toluene (20 mL) and aq sodium bicarbonate (10 mL, saturated solution) under argon was added a solution of phenyboronic acid (153 mg in 5 ml abs ethanol). Tetrakis(triphenylphosphine) palladium(O) (36 mg) was added, and the solution was heated to reflux (~80°C) for 18 hours, cooled to room temperature and partitioned between aqueous sodium hydroxide (100 mL, 3N) and ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (2 x 200 mL) and the organic layers were combined, dried (MgS04) and concentrated in vacuum to a crude oil which was purified using flash chromatography (silica, 10:0.5: 0.05 ethyl acetate : methanol : ammonium hydroxide) to provide Compound A (90 mg, 45 %) as a waxy solid. B. 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methyl- sulfonyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
Compound B was prepared as a white solid in 40% yield from Compound A was described in the following sequence: Compound A of Example 78, with stirring for 18 hours and no chromatography; Compound B of Example 78. MS: (M+H)+473 Analy Jsis calculated for C 27 H 28 N O, * . 0.5 H 2O . 0.8 TFA.
Calc'd: C, 59.97; H, 5.24; N, 9.78; S, 5.60; F, 7.96. Found: C, 59.94; H, 4.87; N, 8.21 ; S, 4.48; F, 7.86.
Example 377
Figure imgf000326_0001
1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N-(1 - naphthalenyl)-7-phenyl-4H-1 ,4-benzodiazepine-4-carboxamide, monohydrochloride.
A. 1 ,2,3,5-Tetrahydro-N-(1 -naphthalenyl)-7-phenyl-4H-1 ,4- benzodiazepine-4-carboxamide
Compound B of Example 12 (148 mg, 0.66 mmol) was added to 1 - naphthylisocyanate (116 mg, 0.66 mmol) in 3 mL of dry CH2CI2 under argon and the mixture was stirred for 16 hours and concentrated to give crude compound A (267 mg). B. 1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N-(1 - naphthalenyl)-7-phenyl-4H-1 ,4-benzodiazepine-4-carboxamide, monohydrochloride
Compound B was prepared as a light pink solid in 46% yield from Compound A as described for Compound D of Example 1. mp 170-177°C dec.
MS: (M+H)+474 Analysis calculated for C30H27N5O • 1.2 HCl • 0.6 H2O • 0.25 Et2θ.
Calc'd: C, 68.11 ; H, 5.88; N, 12.81 ; Cl, 7.78. Found: C, 68.02; H, 5.92; N, 12.61 ; Cl, 7.75.
Figure imgf000327_0001
(S)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
A solution of the free base of Example 78 (100 mg, 0.31 mmol) in isopropanol (5 mL) was purified using chiral-phase preprative HPLC
(chiralpak AD column produced by Chiral Technologies Inc. ( 50 mm x 500 mm), 25:75:0.1 isopropanol:hexane:triethylamine, flow rate 55 ml/min) to provide isomer A at 36 min (18 mg, 13%, free base of Example 378) and isomer B at 54 min retention times. The hydrochloride was prepared as described for Compound D of Example 224. MS: (M+H)+476 Analysis calculated for C21H23N402SBr 1.2H2O . 0.7 HCl.
Calc'd: C, 47.43; H, 4.85; N, 10.54; S, 6.03; Br, 15.03; Cl, 8.00. Found: C, 47.71 ; H, 4.66; N, 9.71 ; S, 5.59; Br, 12.54, Cl, 8.14. Example 379
Figure imgf000328_0001
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2,3- dimethylbenzoyl)-1 H-1 ,4-benzodiazepin-8- yljcyclohexanecarboxamide, dihydrochloride.
A. 8-Nitro-2,3,4,5-tetrahydro-4-Fmoc-1 H-1 ,4- benzodiazepine
FmocOSu (19.0 g, 56.4 mmol) was added to a -10°C solution of the dihydrochloride of Compound D of Example 22 (15.0 g, 56.4 mmol) and DIEA (19.6 ml, 113 mmol) in dichloromethane (100 ml). The mixture was stirred at 0°C for 2h, quenched with 10% NaHC03 (100 ml) and extracted with CH2CI2 (2X100 ml). The combined organic extracts were washed with 1 N HCl (2X100 ml). The organic fraction was washed with 10% NaHCO3 (2X100 ml), dried (MgS04), filtered and concentrated under vacuum. The residue was triturated with ether and dried under vacuum to afford Compound A as a white solid (15.6 g, 67%). MS: (M+H)+416
B. 8-Nitro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
Fmoc-1 H-1 ,4-benzodiazepine
4-Formylimidazole (7.16 g, 74.6 mmol) was added to a solution of Compound A (15.5 g, 37.3 mmol) with 4A molecular sieves (6 gm) in 1/1 CH-jClj/AcOH (200 ml). The mixture was stirred at rt for 2h. Sodium triacetoxyborohydride (11.9 g, 56 mmol) was added portionwise over 15 minutes and the resulting solution was stirred for 3h. 4-Formylimidazole (1.10 g, 11.5 mmol) was added and the mixture was stirred for 1h. Sodium triacetoxyborohydride (2.39 g, 11.3 mmol) was added portionwise over 15 minutes and the resulting solution was stirred for 16h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in CH2CI2 (100 ml) and quenched with 10% NaHC03 (200 ml). The organic fraction was separated and the aqueous layer extracted with CH2CI2 (2X100 ml). The combined organic fractions were dried (MgSO , filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with CH2CI2, discarding all fractions and removing the product with 9/1 CHCIg/MeOH) to afford Compound B (17.6 g, 95 %) as a glassy solid. (M+H)+ 496
C . N-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(2,3- dimethylbenzoyl)-1 H-1 ,4-benzodiazepin-8-yl]cyclohexane- carboxamide, dihydrochloride
A solution of Compound B (12.0 g, 24.2 mmol) in DCE (70 ml) was added to 2-chlorotritylchloride polystyrene resin (13.9 g, 24.2 mmol, 1.74 mmol/g load, Advanced ChemTech) in a glass shaker flask, previously swollen with DCE (50 ml) at room temperature. DIEA (4.19 ml, 24.2 mmol) was added and the mixture was shaken at room temperature for 72h. The resin was filtered and washed with DCE (4X50 ml). The resin was washed with MeOH (4X50 ml), filtered and dried under vacuum to afford Compound B attached to resin via the imidazole group (23.1 g, 89%; loading 0.90 mmol/g based on nitrogen analysis) as orange beads. The resin (23.1g, 23.1 mmol) was swelled with DMF (50 ml) for 15 minutes. Piperidine (50 ml) was added and the mixture was shaken for 5h, filtered, washed with DMF (50 ml) and filtered. DMF (50 ml) was added and the mixture was shaken for 15 minutes. Piperidine (50 ml) was added and the mixture was shaken for 5h. The resin was filtered, washed and filtered with successive treatments of DMF (3X50 ml), CH2CI2 (3X50 ml), and MeOH (3X80 ml) allowing 15 minutes to equilibrate resin after addition of each solvent. The resin was dried under vacuum to afford deprotected resin bound material (18.2 g 80%, loading 1.17 mmol/g based on nitrogen analysis) as orange beads. Resin (0.275 g, 0.322 mmol) was placed in a 25 ml Varian Bond Elut Reservoir tube fitted with a 20 mM Varian frit and polypropylene leuer tip stopcock. The tube was attached to Vac Elut SPS 24 on a Innova 2000 Platform Shaker. The resin was swelled with CH2CI2 (2 ml) for 15 minutes. A 0.77 M DMF solution of 2, 3 dimethylbenzoic acid (1.25 ml) was added to the resin. A 0.92 M DMF solution of HOAT (1.04 ml) and a 0.46 M CH2CI2 solution of DIC (2.08 ml) were added to the resin mixture. The platform shaker mixed the solid phase reaction @ 285 RPM for 16h. The tube was filtered and the resin was washed and filtered with successive treatments of DMF (3X5 ml), CH2CI2 (3X5 ml), and MeOH (3X5 ml) allowing 15 minutes to equilibrate resin after addition of each solvent. The resin was again swelled with CH2CI2 (2 ml) for 15 minutes. A 0.77 M DMF solution of 2, 3 dimethylbenzoic acid (1.25 ml) was added to the resin. A 0.92 M DMF solution of HOAT (1.04 ml) and a 0.46 M CH2CI2 solution of DIC (2.08 ml) were added to the resin mixture. The platform shaker mixed the solid phase reaction @ 285 RPM for 16h. The tube was filtered and the resin was washed and filtered with successive treatments of DMF (3X5 ml), CH2CI2 (3X5 ml), and MeOH (3X5 ml) allowing 15 minutes to equilibrate resin after addition of each solvent. This sequence of events afforded N4-acylated resin-bound material that was carried on to the next step. The resin was swelled with 1/1 DMF/CH2CI2 (2 ml) for 15 minutes. A 0.23 M solution of SnCI2.2H20 (0.222 g, 0.97 mmol), and TEA (0.672 ml, 4.83 mmol) in CH2CI2 (4 ml) was added to the resin mixture. The resin mixture was shaken for 16h. The tube was filtered and the resin was washed and filtered with successive treatments of DMF (3X5 ml), CH2CI2 (3X5 ml), and MeOH (3X5 ml) allowing 15 minutes to equilibrate resin after addition of each solvent. The resin was swelled with 1/1 DMF/CH2CI2 (2 ml) for 15 minutes and the entire procedure for this step was repeated two times. This sequence of events afforded 8-amino resin-bound material that was carried on to the next step. The resin was swelled with CH2CI2 (2 ml) for 15 minutes. A 0.77 M DMF solution of cyclohexylcarboxylic acid (1.25 ml) was added to the resin. A 0.92 M DMF solution of HOAT (1.04 ml) and a 0.46 M CH2CI2 solution of DIC (2.08 ml) were added. The platform shaker mixed the solid phase reaction @ 285 RPM for 16h. The tube was filtered and the resin was washed and filtered with successive treatments of DMF (3X5 ml), CH2CI2 (3X5 ml), and MeOH (3X5 ml) allowing 15 minutes to equilibrate resin after addition of each solvent. The resin was again swelled with CH2CI2 (2 ml) for 15 minutese. A 0.77 M DMF solution of cyclohexylcarboxylic acid (1.25 ml) was added to the resin. A 0.92 M DMF solution of HOAT (1.04 ml) and a 0.46 M CH2CI2 solution of DIC (2.08 ml) were added to the resin mixture. The platform shaker mixed the solid phase reaction @ 285 RPM for 16h. The tube was filtered and the resin was washed and filtered with successive treatments of DMF (3X5 ml), CH2CI2 (3X5 ml), and MeOH (4X5 ml) allowing 15 minutes to equilibrate resin after addition of each solvent. This sequence of events afforded 8-acylated resin-bound material that was carried on to the next step. Resin was swelled with CH2CI2 (4 ml) for 15 minutes. Triethylsilane (0.51 ml, 3.2 mmol, 10 equiv) was added. The resin mixture was treated with TFA (4 ml) and the reaction was shaken for 1h. The filtrate was collected by vacuum filtration. The resin was again swelled with CH2CI2 (4 ml) for 15 minutes. Triethylsilane (0.51 ml, 3.2 mmol, 10 equiv) was added. The resin mixture was treated with TFA (4 ml) and the reaction was shaken for 1h. The filtrate was collected by vacuum filtration. The combined filtrates were concentrated under vacuum. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and appropriate fractions were collected and concentrated under vacuum. The residue was dissolved in CH3CN (2 ml), treated with 1N HCl (1 ml) and concentrated under vacuum four times. The residue was dissolved in CHgCN (2 ml), treated with 1 N HCl (1 ml) and the solution was lyophilized to afford Example 379 (0.0075 g, 4% overall yield) as a glassy solid. MS (M+H)+ 486
Example 380
Figure imgf000331_0001
(R)-7-Cyano-N-[2-(dimethylamino)ethyl]-2,3,4,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-N-methyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine-4-carboxamide, trifluoroacetate (1 :2).
A. (R)-7-Cyano-2,3,4,5-tetrahydro-4-(4-nitrophenyl- oxycarbonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
To a solution of Compound C of Example 248 (200 mg, 0.76 mmol) in THF (20 mL) under argon was added 4-nitrophenylchloroformate (0.88 mL, 0.76 mmol). The solution was stirred for 8 hours, poured into aqueous hydrochloric acid (150 mL, 1N), extracted with ethyl acetate (2 x 150 mL), dried (MgS04), and concentrated to an oil which was purified using flash chromatography (50 g silica, 2 : 1 hexane : ethyl acetate) to provide Compound A (230 mg, 70 %) as a clear oil.
B. (R)-7-Cyano-N-[2-(dimethylamino)ethyl]-2,3,4,5- tetrahydro-N-methyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-4- carboxamide
A solution of Compound A (110 mg, 0.26 mmol), in N,N,N'- trimethyethylene diamine (2 mL) was heated in a sealed pressure tube at 110°C for 18 hours. After cooling to room temperature, the solution was poured into aqueous sodium hydroxide (100 mL, 1N), extracted with ethyl acetate (2 x 150 mL), dried (MgSO4) and concentrated under vacuum to afford crude Compound B as a brown paste (yield >100 %).
C . (R)-7-Cyano-N-[2-(dimethylamino)ethyl]-2,3,4,5- tetrahydro-1-(1 H-imidazol-4-ylmethyl)-N-methyl-3- (phenylmethyl)-l H-1 ,4-benzodiazepine-4-carboxamide, trifluoroacetate (1 :2)
A solution of Compound B (140 mg, 0.35 mmol), 4-formyl imidazole ( 68 mg, 0.7 mmol), dichloroethane (2 mL) and acetic acid (2 mL) was stirred at room temperature for 30 min and sodium triacetoxyborohydride (150 mg, 0.7 mmol) was added. The solution was heated to 60°C, stirred for 18 hour, and additional portions of 4-formyl imidazole and sodium triacetoxyborohydride were added (0.2 mmol each, 4 portions over 8 hours); the mixture was diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 ml, cone), and stirred for an additional 30 min. The mixture was extracted with ethyl acetate (2 x 25 mL) and the combined organic extracts were washed with aqueous sodium bicarbonate (25 ml, saturated solution), and then ammonium chloride (25 mL, sat aqueous solution), dried (Na2Sθ4), and concentrated in vacuo to a semi-solid. The crude was purified by preparative HPLC (aqueous methanol gradient containing 0.1% TFA, C-18 column) and lyophilized to provide Compound C as a white solid (80 mg,
48%).
MS: (M+H)+471 Analysis calculated for C27H33N70 1.1 H20 . 2.1 TFA.
Calc'd: C, 51.27; H, 5.14; N, 13.42; F, 16.38. Found: C, 51.60; H, 4.93; N, 13.47; F, 16.28.
Figure imgf000333_0001
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-2-oxo-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
A. N-((2-Nitrophenyl)-methyl)-phenylalanine methyl ester
To a solution of 2-nitrobenzaldehyde (5g, 33 mmol) in acetic acid (150 mL) was added D,L phenylalanine-O-methyl ester (8.54 g, 40 mmol) and then sodium acetate (3.5 g, 43 mmol). Sodium triacetoxyborohydride (9.09 g, 43 mmol) was slowly added and the mixture was heated to 80°C for four hours, cooled to room temperature, concentrated under vacuum to a paste (-20 mL) and dissolved in ethyl acetate (100 mL). The solution was neutralized with saturated sodium carbonate and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried (MgS04), and concentrated to provide Compound A as a brown oil (11.25 g, > 100 %).
B. N-((2-Nitrophenyl)-methyl)-N-(methanesulfonyl)- phenylalanine methyl ester
To a solution of Compound A (1.12 g, 3.5 mmol) in pyridine (10 mL) under argon in an ice bath was slowly added methanesulfonyl chloride (1.08 mL, 14.0 mmol). The solution was warmed to room temperature, poured into aqueous hydrochloric acid (250 mL, 1 N), extracted with ethyl acetate (2 x 200 mL) and the combined organic layers dried (MgS04) and concentrated. The oil was purified by flash chromatography (4:1 hexane:ethyi acetate) to provide Compound B (660 mg, 48%) as a clear oil. C . N-((2-Aminophenyl)-methyl)-N-(methanesulfonyl)- phenylalanine methyl ester
A mixture of Compound B (660 mg, 1.68 mmol), tin (II) chloride (1.52 g, 6.7 mmol) and ethyl acetate (75 mL) was stirred at room temperature for 18 hours and quenched with aqueous and then solid potassium carbonate (5 mL, then 5 gms). The mixture was filtered, the filtrate partitioned and the organic phase dried (MgS04), concentrated in vacuum, and purified using flash chromatography (3:1 hexane : ethyl acetate) to provide Compound C (315 mg, 52 %) as a clear oil.
D. N-((2-Amino-5-bromophenyl)-methyl)-N-(methane- sulfonyl)-phenylalanine methyl ester
Compound D was prepared as a white solid in 60% yield from Compound C as described for Compound A of Example 262 except that the product was purified by crystallization from methanol.
E. N-[[2-(((lmidazol-4-yl)-methyl)-amino)-phenyl]-methyl]-N- (methanesulfonyl)-phenylalanine methyl ester Compound E was prepared as a semi-solid in 100% yield from
Compound D as described for Compound D of Example 1 , with stirring for 4 hours and with the crude free base carried on directly.
F. N-[[2-(((lmidazol-4-yl)-methyl)-amino)-ρhenyl]-methyl]-N- (methanesulfonyl)-phenylalanine
A solution of Compound E (200 mg, 0.38 mmol) and LiOH (80 mg, 2 mmol) in THF (6 mL), methanol (1 mL) and water (1 mL) was stirred at room temperature for 1 hour, concentrated under vacuum to 2 mL and poured into aqueous hydrochloric acid (20 mL, aqueous). The mixture was extracted with ethyl acetate (2 x 50 mL) and the combined organic layers were dried (MgS04), and concentrated to provide Compound F (150 mg, 78 %) as a clear oil. G. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
4-(methylsulfonyl)-2-oxo-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate
A mixture of Compound F (150 mg, 0.29 mmol), DMF (3 mL), DIEA (0.66 mL, 0.725 mmol), and BOP (193 mg, 0.43 mmol) was stirred at room temperature for 3 hours. The mixture was partitioned between sodium carbonate (100 ml, sat soln) and ethyl acetate (100 mL), the aqueous phase was extracted with ethyl acetate (2 x 50 mL) and the combined organic layers were dried (MgS04) and concentrated. The residue was purified by preparative HPLC (aqueous methanol gradient containing 0.1 % trifluoroacetic acid, C-18 column) and lyophilized to provide Compound G as a white solid (65 mg, 46 %).
MS: (M+H)+490
Analysis calculated for C21H21N403 » 1.1 H20 • 1.0 TFA. Calc'd: C, 44.33; H, 3.91 ; N, 8.99; S, 5.14; Br, 12.82. Found: C, 44.29; H, 3.59; N, 8.74; S, 5.05; Br, 12.78.
Figure imgf000335_0001
(R)-7-Cyano-4-(2-f uranylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :1 ).
A. (R)-7-Cyano-4-(2-furanylcarbonyl)-2,3,4,5-tetrahydro-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine
Compound A was prepared as a oil in 100% yield from Compound C of Example 248 and furan-2-carboxylic acid as described for Compound G of Example 381 , with stirring for 18 hours, workup with citric acid, and no purification.
B. (R)-7-Cyano-4-(2-furanylcarbonyl)-2,3,4,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate (1 :1 )
Compound B was prepared as a white solid in 7% yield from Compound A as described for Compound C of Example 380. MS: (M+H)+438 Analysis calculated for C26H23N5O2 • 2.0 H2O • 1.0 TFA.
Calc'd: C, 57.24; H, 4.80; N, 11.92. Found: C, 57.22; H, 4.26; N, 11.74.
Figure imgf000336_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(4- nitrophenyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluroracetate.
Example 383 was prepared as a white solid in 3% yield from 4- nitrobenzene sulfonylchloride and Compound C of Example 248 by the following sequence: Compound C of Example 350, except that the reaction was run at room temperature and no purification was performed; Compound C of Example 380. MS: (M+H)+529 Example 384
Figure imgf000337_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[[4- (4-methyl-1 -piperazinyl)phenyl]sulf onyl]-3-(phenylmethyl)-1 H- 1 ,4-benzodiazepine, trifluoroacetate.
A. (R)-7-Cyano-2,3,4,5-tetrahydro-4-[[4-(4-methyl-1 - piperazinyl)phenyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a mixture of (R)-7-cyano-2,3,4,5-tetrahydro-4-[(4- fluorophenyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (200 mg, 0.48 mmol, prepared as described in Example 291 ) in DMF (2 mL) was added N-methylpiperazine (2 mL). The solution was heated to 110°C and stirred for six hours, poured into aqueous hydrochloric acid (150 mL, 1 M) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried (MgS04), concentrated and the residue crystallized from dichloromethane to provide Compound A (50 mg, 21 %) as a grey solid.
B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-[[4-(4-methyl-1-piperazinyl)phenyl]sulfonyl]-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, trifluoroacetate
Compound B was prepared as a white solid in 65% yield from Compound A as described for Compound C of Example 380, with stirring at room termperature.
MS: (M+H)+581
Analy 1sis calculated for C 32 H 35 N 70, 3S • 2.0H 2 O • 2.0 TFA.
Calc'd: C, 51.12; H, 4.89; N, 11.59; S, 3.79. Found: C, 50.83; H, 4.68; N, 11.43; S, 4.47. Example 385
Figure imgf000338_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- [[(4-dimethylamino)phenyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate.
A. (R)-7-Cyano-2,3,4,5-tetrahydro-4-[[(4- dimethylamino)phenyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
A solution of (R)-7-cyano-2,3,4,5-tetrahydro-4-[(4- fluorophenyl)sulfonyl]-3-(phenylmethyl)-1H-1 ,4-benzodiazepine (200 mg, 0.48 mmol, prepared as described in Example 291) in dimethylamine (2 mL, 2 M in THF) was stirred at 60°C in a sealed pressure tube for 24 hours. Additional dimethylamine (4 mL, 2 M in THF) was added and the solution was stirred for an additional 6 hours. The reaction was concentrated to a paste under vacuum and the residue crystallized from methanol to provide Compound A (50 mg, 25%) as a grey solid.
B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-[[(4-dimethylamino)phenyl]sulfonyl]-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, trifluoroacetate
Compound B was prepared as a white solid in 43% yield from Compound A as described for Compound C of Example 380.
Analysis calculated for Calcd for C2gH30N6O2S « 1.3 H20 • 0.9 TFA.
Calc'd: C, 56.68; H, 5.17; N, 12.88; S, 4.91 ; F, 7.80. Found: C, 56.36; H, 5.07; N, 12.51 ; S, 5.39; F, 7.78. Example 386
Figure imgf000339_0001
(R)-7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2, 3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, dihydrochloride.
A. (R)-7-Bromo-4-[ethenylsulfonyl]-2,3,4,5-tetrahydro-3- (phenylmethyl)-4H-1 ,4-benzodiazepine
To a solution of Compound B of Example 224 (10 g, 31.5 mmol) in dichloromethane (120 mL) at 0°C was added dropwise a solution of 2- chloroethanesulfonyl chloride (3.2 mL, 30 mmol) in dichloromethane (10 mL). DIEA (5.2 mL, 30 mmol) was added dropwise. After 15 min, 2- chloroethanesulfonyl chloride (1.5 mL, 15 mmol) followed by DIEA (10.4 mL, 60 mmol) were added. The mixture was allowed to warm to rt and poured into water (80 mL). The organic layer was separated, washed with 1 N HCl and saturated aqueous NaHCOg (80 mL each), dried (MgS04) and concentrated in vacuo to afford Compound A as a yellowish foamy solid (15.2 g). MS: (M+H)+ = 406+
B. (R)-7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5- tetrahydro-3-(phenylmethyl)-4H-1 ,4-benzodiazepine
A flask was charged with Compound A (7g) and a THF solution of dimethylamine (2M, 20 mL). The flask was stoppered and the mixture was stirred 18 hr, concentrated and purified by silica gel column chromatography eluting with 20% acetone in chloroform to afford Compound B (48% from Compound B of Example 224). C . (R)-7-Bromo-4-[[2-(dimethylamino)ethyl]sulf onyl]-2, 3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4- benzodiazepine, dihydrochloride
To a solution of Compound B (5.3 g, 11.7 mmol) in dichloromethane (100 mL) were added acetic acid (15 mL) and 4- formyiimidazole (1.15 g, 12 mmol). After 10 min, sodium triacetoxyborohydride (2.54 g, 12 mmol) was added. After 3 hr, 4- formylimidazole (0.5 g, 5.8 mmol) and borohydride (1.2 g, 5.5 mmol) were added. After 18 hr, aldehyde (0.5 g) and borohydride (1.2 g) were added. After 5 hr, the mixture was concentrated. Aqueous ammonia (100 mL) and chloroform (100 mL) were added to the residue and the mixture was stirred vigorously for 0.5 hr. The two layers were separated and the organic layer was washed again with aqueous ammonia (100 mL). The combined aqueous layer was extracted with chloroform (100 mL), the two organic extracts were combined, dried (K2C03), and concentrated. The residue was purified by flash silica gel column chromatography (step gradient of 5% and 10% MeOH in chloroform) to afford a solid which was dissolved in dichloromethane (50 mL) and HCl gas was bubbled through the solution. The mixture was concentrated in vacuo to afford a solid which was dissolved in water and lyophilized to afford Compound C (5.2 g, 73 %). MS: (M+H)+ 532
Analysis calculated for C24H30BrN5O2S. 2HCI. Calc'd: C, 47.61 ; H, 5.33; N, 11.57. Found: C, 47.36; H, 5.45; N, 11.34.
Example 387
Figure imgf000341_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(3-pyridinylsulfonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 387 was prepared as a yellow solid in 15% yield from Compound C of Example 248 and 3-pyridinesulfonyl chloride as described for Example 284. MS: (M+H)+485
Example 388
Figure imgf000341_0002
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzo-diazepine, dihydrochloride.
BuLi (1.0 M in THF, 5 mmol) was added to a solution at -78°C of the free base of Example 224 (0.104 g, 0.19 mmol) in THF (10 mL). After 5 min., H20/THF (1 :1 , 10 mL) was added. The solution was saturated with NaCl. The aqueous layer was extracted with CH2CI2. The combined organic phases were dried over Na2S04. Evaporation of solvent gave a solid which was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted into its HCl salt to afford 25 mg (30%) of Example 388 as a yellow solid. MS: (M+H)+397
Example 389
Figure imgf000342_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-4- yl)methyl]-4-(methy!sulfonyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
NaH (60% in mineral oil, 1 g) was added to a solution at -10°C of the free base of Example 224 (0.23 g, 0.19 mmol) in DMF/THF (1 :1 , 10 mL). After 20 min., Mel (0.7 mL) was added. The mixture was stirred at -5°C for 1 hr, quenched with MeOH (5 mL) and diluted with CH2CI2 (20 mL). The organic phase was washed with 2.5% NaOH. The organic phase was dried over Na2S04. Evaporation of solvent gave a solid which was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) followed by preparative TLC (8% MeOH, 2% iPr2NH in CH2CI2) to provide 10 mg of Example 389 (10%) as a white solid. MS: (M+H)+491
Figure imgf000343_0001
(R)-4-[[3-(Dimethylamino)propyl]sulfonyl]-2,3,4,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A. (R)-4-[[3-Chloropropyl]sulfonyl]-2,3,4,5-tetrahydro-7- phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine To a solution of Compound D of Example 226 ( 4.7 g, 15 mmol) and
DIEA (7 mL, 40 mmol) in CH2CI2 (40 mL) at 0°C was added slowly 3- chloropropanesulfonyl chloride (2 mL, 16 mmol) in CH2CI2 (5 mL). After 2 hrs, the solvent was evaporated. The residue was dissolved in CH2CI2 (20 mL) and the solution was washed with 1 N NaOH (2x 50 mL), dried and evaporated to provide Compound A as an oil (5.5 g).
B. (R)-4-[[3-Chloropropyl]sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine A solution of Compound A (5.5 g) and 4-formylimidozle (3 g, 30 mmol) in AcOH/ CH2CI2 (1 :5 , 300 mL) was stirred for 1 hr. NaBH(OAc)3 (total 9 g, 42 mmol) was added (3 g every 4 hrs) and the solution was stirred for 12hr. The solvent was evaporated and the residue was treated with 3% NaOH (50 mL). The solid was filtered and washed with water (5x100 mL) and dried to give Compound B (7.5 g). C . (R)-4-[[3-(Dimethylamino)propyl]sulf onyl]-2,3,4,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, dihydrochloride
A solution of Compound B (7 g) and dimethylamine (2.0 M in THF, 75 mL, 150 mmol) in DMF (150 mL) was warmed to 80°C (sealed tube) for
30 hr. The DMF was removed. The residue was passed through a short silica gel colum (5% MeOH, 0.5% NH40H in CH2CI2). The eluant was evaporated and the residue was purified by reverse phase preparative
HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt to provide Compound C as an off white solid (5.0 g, 60% from
Compound D of Example 226)
MS: (M+H)+544
1 H-NMR (CD3OD, 300Mhz) d: 1.80 (m, 2H), 2.8 (m , 2H), 3.0 (m, 4H), 3.20
(m, 2H), 3.60 (m, 2H), 4.30 (m, 1H), 4.6 (m, 2H), 6.8 (d, 7Hz, 1H), 7.1 to 7.6 (m, 13H), 8.92 (s, 1H).
Figure imgf000344_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, trihydrochloride.
Example 391 is Compound C of Example 280. MS(M+H)+244.
Figure imgf000345_0001
4-Butyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, trihydrochloride.
A solution of Example 391 (0.23 g, 0.7 mmol) and butyraldehyde (1 g, 14 mmol) in 1:4 AcOH/CH2CI2 (25 mL) was stirred at rt for 1hr. NaBH(OAc)3 (3.0 g, 14 mmol) was added and stirring was continued for 14 hrs. The reaction was quenched with cone. NH4OH and diluted with 10% iPrOH in CH2CI2 (50 mL). The organic phase was washed with 1N NaOH (2x20 mL), dried over Na2S04 and evaporated to give a yellow solid (0.4 g) which was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt by lyophilizing with 1 N HCl to give Example 392 as a yellow solid (45 mg, 12%). MS (M+H)+400.
Example 393
Figure imgf000346_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[[2- (4-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
A. (R)-7-Bromo-2,3,4,5-tetrahydro-4-[[2-(4- morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine
To a solution of Compound A of Exmaple 386 (0.23 g, 0.34 mmol, 61% pure) in THF (1.5 mL) at rt was added morpholine (0.2 mL). The mixture was stirred 16 hr, diluted with ethyl acetate (15 mL), washed with water and brine (15 mL each), dried and concentrated in vacuo. The residue was purified with flash silica gel column chromatography eluting with 20% acetone in chloroform to afford Compound A as a white solid (130 mg, 77%).
B. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-[[2-(4-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride
A mixture of Compound A (0.060 g, 0.12 mmol), 4-formylimidazole (0.011 g, 0.12 mmol), 3A sieves and AcOH (0.2 mL) in dichloroethane (0.3 mL) was stirred at rt, under argon. After 2 hr, sodium triacetoxyborohydride (0.025 g, 0.12 mmol) was added. After stirring for 16 hr, the mixture was diluted with CHCI3 (10 mL), NH4OH (5 mL) and NaHC03 (5 mL), and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCIg (2 x 20 mL). The combined organic extracts were washed with NaHCOg, water , brine (3 x 10 mL each), dried over MgS04, filtered and concentrated. The residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1 % TFA). The appropriate fractions were concentrated under vacuum. The residue was evaporated from MeOH (1 mL) and 1 N HCl (1 mL) 3 times. The residue was dissolved in water and lyophilized to afford Compound B as a light yellow solid (0.019 g, 28 %). MS (M+H)+574.
Example 394
Figure imgf000347_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1-[(1-methyl-1 H-imidazol-5- yl)methyl]-4-[[2-(4-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 394 was prepared as a light yellow solid in 23% yield from Compound A of Example 393 and N-methyl-5-formylimidazole as described for Compound B of Example 393, with stirring under reflux for 7 hours before addition of hydride, cooling to rt, adding hydride, and stirring 16 hours after addition of hydride. MS (M+H)+588.
Example 395
Figure imgf000348_0001
(R)-7-Cyano-1 -(1 H-imidazol-4-ylmethyl)-4-(4- morpholinylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-7-Cyano-4-(4-morpholinyisulfonyl)-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine To a solution of Compound C of Example 248 (263 mg, 1 mmol) in acetonitrile (2 mL) at rt under argon were added morpholinesulfamoyl chloride (371 mg, 2 mmol) and DIEA (0.35 mL, 2 mmol). The resulting brown mixture was stirred for 65 hr and concentrated, and the residue was partitioned between 1 N HCl and chloroform (10 mL each). The organic layer was separated, washed with saturated NaHCOg, dried (MgS04) and concentrated. The residue was purified by flash silica gel column eluting with a step gradient of 40% and 50% EtOAc in hexanes to afford Compound A (95 mg, 71%) as a pale yellow solid. MS (M+H)+ = 413
B. (R)-7-Cyano-1 -(1 H-imidazol-4-ylmethyl)-4-(4- morpholinylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride
To a solution of Compound A (206 mg, 0.5 mmol) in 1 ,2- dichloroethane (2 mL) at RT under argon were added 4-formylimidazole (380 mg, 4 mmol), HOAc (0.5 mL) and 3A sieves. The mixture was warmed to 50°C and sodium triacetoxyborohydride (330 mg, 1.5 mmol) was added. After 18 hr, more hydride (212 mg, 1 mmol) was added. After 5 more hrs, the mixture was cooled to RT, filtered through celite and carefully treated with 30% NH4OH (10 mL) and chloroform (10 mL). The mixture was vigorously stirred for 1 hr, the organic layer was separated and washed with 15% ammonia solution (15 mL), dried (K2C03) and concentrated. The brown oil obtained was purified by silica gel column chromatography eluting wih 5% MeOH in chloroform to afford the free base of Compound B (150 mg, 61%) as a white solid. 26 mg of this solid was treated with 1N HCl in ether followed by concentration in vacuo to afford Compound B (28 mg). MS (M+H)+ = 493; (M-H) = 491.
Example 396
Figure imgf000349_0001
(R)-7-Cyano-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4-[(4- morpholinyl)sulf onyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. (R)-7-Cyano-1 -[(1-triphenylmethyl-1 H-imidazol-4- yl)methyl]-4-[(4-morpholinyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine To a solution of the free base of Example 395 (120 mg, 0.24 mmol) in acetonitrile (2 mL) at RT under argon were added trityl chloride (83 mg, 0.3 mmol) and DIEA (0.053 mL, 0.3 mmol). The mixture was refluxed for 4 hr, cooled to RT and concentrated. The residue was dissolved in chloroform (15 mL) and washed with water and saturated NaHC03 (15 mL each). The organic layer was dried (MgSOJ, and concentrated. The residue was washed with warm hexanes (2 x 5 mL) to afford Compound A (178 mg, 100%) as a pale yellow solid. B. (R)-7-Cyano-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4-[(4- morpholinyl)sulfonyl]-3-(pheny lmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride
To a solution of Compound A (170 mg, 0.23 mmol) in dichloromethane (2 mL) at -78°C under argon was added methyl trifiate (0.027 mL, 0.24 mmol). After 1 hr, the cold bath was removed and replaced with ice bath (0°C). After 2 hr, 50% aqueous acetic acid (2 mL) was added and the mixture was refluxed 40 min. Chloroform and saturated NaHCOg (10 mL each) were added and the mixture was stirred carefully until effervescence subsided. Solid K2C03 was added carefully until pH 11 of the aqueous layer was achieved. The organic layer was separated, dried (K2C03) and concentrated in vacuo. The solid residue was washed with warm hexanes and ether (2 X 10 mL each). The solid was dissolved in EtOAc (5 mL) and 1 N HCl in ether (2 mL) was added. The precipitate was collected and washed with EtOAc (3 X 5 mL). The solid was dried in vacuo at 40°C to afford Compound B as a pale yellow solid (110 mg, 84%). MS: (M+H)+ = 507.
Analysis calculated for C26H30N6O3S • 1.7 HCl. Calc'd: C, 54.75; H, 5.61 ; N, 14.73. Found: C, 55.15; H, 5.68; N, 14.29.
Figure imgf000350_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(4- aminophenyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. To a stirred solution of the free base of Example 383 (5 mg) in ethyl acetate was added SnCI2. The solution was stirred at room temperature for 18h. NH40H was added, followed by MgS04. The suspension was filtered, and the filtrate was concentrated in vacuo. The residue was dissoved in methanol, 1N HCl in ether was added. The solvent was removed to give 2.0 mg Example 397 (40%) as a yellow solid .
Example 398
Figure imgf000351_0001
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(4- pyridylthio)acetyl]-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride.
Example 398 was prepared from Compound B of
Example 33 as described for Examples 101-201. MS (M+H)+ 456.
Example 399
Figure imgf000352_0001
N-(4-Chlorophenyl)-N'-cyano-1 ,2,3,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-7-phenyl-4H-1 ,4- benzodiazepine-4-imidamide, monohydrochloride.
A. N-(4-Chlorophenyl)-N'-cyano-1 ,2,3,5- tetrahydro-7-phenyl-4H-1 ,4-benzodiazepine-4- imidamide
To a stirred solution of Compound B of Example 12 (110 mg, 0.5 mmol) in DMF was added sequentially N-(4- chlorophenyl)-N'-cyanothiourea (130 mg, 0.62 mmol), and EDC (120 mg, 0.61 mmol). The solution was stirred at room temperature for 18 h and partititoned between ethyl acetate and sat'd NH4CI solution. The organic layer was separated, washed with saturated NaHC03 solution and brine, dried, and concentrated. The residue was crystalized from MeOH to give Compound A as a solid (150 mg, 75%). MS: 402 (M+H).
B. N-(4-Chlorophenyl)-N'-cyano-1 , 2,3,5- tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4H-
1 ,4-benzodiazepine-4-imidamide, monohydrochloride
Compound B was prepared as a solid in 78% yield from Compound A as described for Compound D of Example 1. MS: 482 (M+H)
Analysis calculated for C27H23N7CI»2.2HCI»2H20. Calc'd: C, 54.30; H, 4.93; N, 16.42; Cl, 18.99. Found: C, 54.57; H, 4.90; N, 16.76; Cl, 18.90.
Example 400
Figure imgf000353_0001
4-Acetyl-7-bromo-1 ,2,4,5,1 ',3'-hexahydro-1 -(1 H-imidazol-4- ylmethyl)spiro[3H-1 ,4-benzodiazepine-3,2'-[2H]indene], dihydrochloride.
A. N-[(2-Amino-5-bromophenyl)carbonyl]-2-amino-2- indanecarboxylic acid
A solution of 2-amino-2-indanecarboxylic acid (680 mg, 4.15 mmol), bromoisatoic anhydride (1.0 g, 4.15 mmol) and pyridine»HCI (2.0 g, 1.72 mmol) in pyridine (30 mL) was refluxed for 4h, cooled and concentrated. The residue was partitioned between water (200 mL) and ethyl acetate (200mL). The organic layer was washed with water (3X100mL), brine (50 mL), dried (MgS04) and concentrated to yield compound Compound A as a yellowish glass (350 mg, 22 %). MS (M+H)+ 375.
B. 7-Bromo-1 ,2,4,5,1 \3'-hexahydro-spiro[3H-1 ,4- benzodiazepin-2,5-dione-3,2'-[2H]indene]
A solution of Compound A (350 mg, 0.93 mmol), EDC (203 mg, 1.02 mmol), DIEA (0.35 mL, 2.00 mmol) and HOBt (135 mg, 1.00 mmol) in DMF (10 mL) was stirred for 16 h and poured into water (100 mL). The mixture was extracted with ethyl acetate (2X50 mL). The combined ethyl acetate layers were washed with water (3X100 mL), brine (100 mL), dried (MgSθ4) and concentrated to yield compound Compound B as a brown glass (150 mg, 45 %). MS (M+H)+ 358. C . 7-Bromo-1 ,2,4,5,1 ,,3'-hexahydro-spiro[3H-1 ,4- benzodiazepine-3,2'-[2H]indene]
To a solution of Compound B (150 mg, 0.42 mmol) in THF (10 mL) was added borane (1M in THF, 3 mL, 3 mmol). The solution was refluxed for 3h and cooled to room temperature. Methanol (5 mL) was added and the solution was concentrated. 5N HCl (10 mL) was added and the mixture was refluxed for 4h, cooled to room temperature, neutralized to pH 6 with 50% NaOH and extracted with methylene chloride (3X50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSθ4) and concentrated to yield compound C as a slightly yellow glass (70 mg, 50%). MS (M+H)+ 330.
D . 4-Acetyl-7-bromo-1 ,2,4,5,1 \3'-hexahydro-spiro[3H-1 ,4- benzodiazepine-3,2'-[2H]indene]
Compound C (70 mg, 0.21 mmol) was dissolved in THF (5 mL) and DIEA (37 μL, 0.21 mmol) was added followed by acetyl chloride (15 μL, 0.21 mmol). The solution was stirred for 30 min, concentrated, dissolved in ethyl acetate (50 mL) and washed with water (3X20 mL). The organic layer was dried (MgSθ4) and concentrated to yield Compound D as a light brown glass.
E . 4-Acetyl-7-bromo-1 ,2,4,5,1 ',3'-hexahydro-1 -(1 H- imidazol-4-ylmethyl)spiro[3H-1 ,4-benzodiazepine-3,2'- [2H]indene], dihydrochloride
Compound D and 4-formylimidazole were dissolved in 1 ,2-DCE (5 mL) and acetic acid (0.5 mL) was added followed by sodium triacetoxyborohydride. The mixture was stirred at 50°C for 2h and saturated NaHCθ3 (5 mL) was added. The mixture was concentrated and the residue was partitioned between water (20 mL) and ethyl acetate (20mL). The organic layer was washed with water (10mL), brine (10 mL), dried (MgSθ4), concentrated and purified by RP preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Fractions containing the desired product were combined, concentrated and lyophilized. This lyophilate was dissolved in methanol (0.5 mL) and 1 N HCl (5mL). This mixture was concentrated and lyophilized. This procedure was repeated to provide Compound E as a white solid (12 mg, 13%) MS (M+H)+ 451.
Figure imgf000355_0001
7-Bromo-4-[3-(dimethylamino)-1 -oxopropyl]-2,3,4,5-tetrahydro-1 (1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate (1 :1).
Example 401 was prepared as a white solid in 6% overall yield from Compound B of Example 224 by the following sequence: EDC/HOBt mediated coupling of acrylic acid in DMF, with purification by flash chromatography; Compound D of Example 232; Compound D of Example 224. MS: (M + H)+ 466.
Figure imgf000355_0002
(R)-2,3,4,5-Tetrahydro-1 -(1 -methyl-1 H-imidazol-5-ylmethyl)-4- (phenylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7- carbonitrile, monohydrochloride. A solution of (R)-7-cyano-2,3,4,5-tetrahydro-1-[(((1 ,1- dimethylethoxy)-carbonyl)-1 H-imidazol-4-yl)methyl]-4-(phenylsulfonyl)-3- (phenylmethyl)-1 H-1 ,4-benzodiazepine (0.23 g, 0.4 mmol, prepared from Example 312 as described for Compound A of Example 234) in CH2CI2 (3 ml) was added to a cooled solution of methyl trifiate (2 mL, 17.6 mmol) in CH2CI2 (10 mL) at -78° C over 30 min. The solution was slowly warmed to 0°C in 4 hrs. PBS Buffer (10 mL) was added and stirred for 20 min. The organic phase was separated. The aqueous layer was extracted with CH2CI2 (2x10 mL). The combined organic layers were dried over Na2S04 and evaporated to give an oil which was purified by RP preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt to afford Example 402 as a yellow solid. (60 mg, 289%) MS (M+H)+ 498
Example 403
Figure imgf000356_0001
2,3,4,5-Tetrahydro-1 -[(1-methyl-1 H-»midazol-5-yl)-methyl]-4- (methyl-sulfonyl)-7-phenyl-3-(pyridin-3-yl-methyl)-1 H-1 ,4- benzodiazepine, hydrochloride (1 :1.5), trifluoroacetate (1 :0.75) salt.
1-Methyl-5-formylimidazole (0.060 g, 0.54 mmol) was added to a solution of 2,3,4,5-tetrahydro-4-(methylsulfonyl)-7-phenyl-3-(pyridin-3-yl- methyl)-1 H-1 ,4-benzodiazepine (0.11 g, 0.27 mmol, prepared as described in Example 328) with 3A molecular sieves (50 mg) in 1/1 DCE: acetic acid (1.8 ml) and the mixture was stirred at 70°C for 1h. Sodium triacetoxyborohydride (0.057 g, 0.27 mmol) was added and the mixture was stirred at 70°C for 30 minutes. 1-Methyl-5-formylimidazole (0.060 g, 0.54 mmol) was added to the mixture and it was stirred at 70°C for 1h. Sodium triacetoxyborohydride (0.057 g, 0.27 mmol) was added and the mixture was stirred at 70°C for 30 minutes. The latter procedure was repeated. The mixture was cooled to room temperature, diluted with methylene chloride (10 ml), filtered and the filtrate concentrated under vacuum. The residue was diluted with 1N NaOH (10 ml) and was stirred at room temperature for 10 minutes. The solution was extracted with CH2CI2 (3X50 ml), the combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by preparative HPLC (gradient of aq MeOH with 0.1% TFA) and the appropriate fractions were isolated and concentrated under vacuum. The residue was evaporated from CH3CN (5 ml) and 1 N HCl (1 ml) 3 times. The residue was dissolved in CH3CN (1 ml) and 1 N HCl (2 ml) and lyophilized to afford Example 403 (0.025 g, 19%) as a white solid. MS: (M+H)+488
Analysis calculated for C27H29N502S . 1.5 HCl . 2.02 H20 . 0.75 TFA. Calc'd: C, 51.54; H, 5.36; N, 10.54. Found: C, 51.27; H, 5.72; N, 10.95.
Example 404
Figure imgf000357_0001
4-[4-(Fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. Example 404 was prepared as a solid in 41% yield from Compound A of Example 364 and 4-fluorobenzenesulfonyl chloride as described for Compound B of Example 364. MS: (M+H)+491
Example 405
Figure imgf000358_0001
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-4- (methyl-sulfonyl)-2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
A. 2,3,4,5-Tetrahydro-2-(2-phenylethyl)-1 H-1 ,4- benzodiazepine To a stirred solution of Compound A of Example 363 (140 mg, 0.52 mmol) in anhydrous THF at rt was added LAH (110 mg). The resultant suspension was stirred at rt for 18h, quenched by addition of ethyl acetate followed by 0.5 mL of concentrated NH40H solution and filtered. The filtrate was concentrated in vacuo to give Compound A as an oil (110 mg, 84%).
B. 2,3,4,5-Tetrahydro-4-(methylsulfonyl)-2-(2-phenylethyl)-
1 H-1 ,4-benzodiazepine
Compound B was prepared as an oil in 61% yield from Compound A as described for Compound C of Example 224. C . 7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-2-(2- phenyl-ethyl)-1 H-1 ,4-benzodiazepine
To a stirred solution of Compound C (80 mg, 0.24 mmol) in CHCI3 was added tetrabutylammonium perbromide (120 mg, 0.24 mmol) in one portion. The mixture was stirred at room temperature for 30 min and evaporated. The residue was partitioned between water and 50% ethyl acetate and hexanes. The organic layer was separated, washed with water, sat'd NH4CI solution, dried, and concentrated to give Compound C as an oil (100 mg, 100%).
D . 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-yl-methyl)- 4-(methylsulfonyl)-2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride
Compound D was prepared as a solid in 92% yield from Compound C as described for Compound D of Example 224. MS: (M+H)+489
Example 406
Figure imgf000359_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 -methyl-1 H-imidazol-5- ylmethyl)-4-[[2-(1-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride.
A. (R)-7-Cyano-2,3,4,5-tetrahydro-4-[ethenylsulfonyl]-3-
(phenyl-methyl)-l H-1 ,4-benzodiazepine
2-Chloroethanesulfonyl chloride (1.85 g, 11.4 mmol) was added to a solution of Compound C of Example 248 (1.0 g, 3.79 mmol) and DIEA (2.6 mL, 15.16 mmol) in dichloromethane (16 mL) at 0°C under argon. After stirring for 16 hr, the reaction was diluted with chloroform (20mL) and NaHCOg (5 mL). The layers were separated, the aqueous layer was extracted with chloroform (2 x 50 mL). The combined organic extracts were washed with NaHCOa (2 x 20 mL) and brine (2 x 50 mL), dried over MgS04, filtered and concentrated, to afford Compound A (1.55 g, 116.5 %).
B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 -methyl-1 H-imidazol-
5-ylmethyl)-4-[[2-(1-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)- 1 H-1 ,4-benzodiazepine, dihydrochloride
Compound B was prepared as a light yellow solid in 12% overall yield by the following sequence: Compound B of Example 353, with chromatography with 1 :1 ethyl acetate:hexanes; Compound C of Example 353, with reaction at room temperature, stirring for 2 days and purification by RP preparative HPLC (gradient of aqueous methanol with 0.1% TFA). MS: (M+H)+535
Example 407
Figure imgf000360_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methyl-sulfonyl)-3-(4-bromophenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Example 407 was prepared from D-4-bromophenylalanine as described for Example 224; the crude product was purified by RP preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Fractions containing the desired product were combined, neutralized with saturated Na2C03 aqueous solution and extracted with CH2CI2. The combined extracts were dried (Na2S04) and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and 1 N HCl solution in ether (10 mL) was added. The solvent was removed in vacuo to give Example 407 as a yellow solid. MS (M+H)+ 555 Example 408
Figure imgf000361_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methyl-sulfonyl)-3-(thiazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 408 was prepared as a yellow solid from D-(thiazol-4- yl)alanine methyl ester as described for Example 407. MS (M+H)+ 484
Example 409
Figure imgf000361_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(propyl-sulfonyl)-3-(thiazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 409 was prepared as described for Example 408, except that propanesulfonyl chloride was used in place of methanesulfonyl chloride. MS (M+H)+ 510. Example 410
Figure imgf000362_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (propylsulf onyl)-3-(4-bromophenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Example 410 was prepared as described for Example 407, except that propanesulfonyl chloride was used in place of methanesulfonyl chloride. MS (M+H)+ 583
Example 411
Figure imgf000362_0002
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethy l)-3- (pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
Example 411 was prepared as a pale yellow solid in 16% yield from Compound A of Example 350 by the following sequence: Compound C of Example 350, with the addition done at 0°C and chromatography with ethyl acetate; Compound D of Example 350, with heating at 60°C. (M+H)+ 476. Analysis calculated for C20H22N5BrO2S • 3.00HC l» 0.17H2O. Calc'd: C, 40.80; H, 4.34; N, 11.89. Found: C, 40.79; H, 4.36; N, 11.79.
Example 412
Figure imgf000363_0001
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-1 -methyl-imidazol-5- ylmethyl)-3-(pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
Example 412 was prepared as a pale yellow solid in 31% yield from (R)-7-bromo-2,3,4,5-tetrahydro-3-(pyridin-3-ylmethyl)-4- (methylsulfonyl)-1 H-1 ,4-benzodiazepine (prepared as described in Example 411) and 1 -methyl-5-formylimidazole as described for Compound D of Example 350, with heating at 60°C. (M+H)+ 490.
Analysis calculated for C21H24N5Br02S • 2.25HCI • 1.38H20. Calc'd: C, 42.23; H, 4.90; N, 11.72. Found: C, 42.23; H, 4.90; N, 11.66.
Example 413
Figure imgf000364_0001
1 ,2,3,4-Tetrahydro-7-bromo-4-[(1 H-imidazo!-4-yl)methyl]-2- phenyl-methyl-1 -(phenylmethyloxycarbonyl)quinoxaline, hydrochloride.
A. N-(2-Nitrophenyl)-phenylalanine
To a suspension of DL-phenylalanine (490 mg, 3 mmol) in water at rt was added sodium bicarbonate (0.84 g, 10 mmol) and 2- fluoronitrobenzene (0.63 mL, 6 mmol). The mixture was heated to 80°C. After 16 hr, ethanol (95%, 3 mL) was added. After 6 hr, the mixture was partially concentrated to remove ethanol and the resulting solution was washed with ethyl acetate and chloroform (10 mL each). The aqueous layer was acidified to pH 1 and extracted with chloroform (2 x 10 mL). The chloroform extracts were combined, dried (MgS04), and concentrated in vacuo to afford Compound A as a solid (0.81 g, 94%). MS (M+H)+ 287
B. N-(2-Nitrophenyl)-phenylalanine, methyl ester To a solution of Compound A (780 mg, 2.7 mmol) in MeOH (15 mL) at rt was added HCl in dioxane (3 mL, 4M). After 18 hr, the mixture was concentrated. The residue was dissolved in chloroform (15 mL) and washed with saturated NaHCOg (10 mL) and brine (15 mL). The organic layer was dried (MgS04) and concentrated in vacuo. The yellow oil was chromatographed (silica, flash, 20% EtOAc/hexanes) to afford Compound B (740 mg, 91%) as a yellow solid. MS (M+H)+ 301
C . 1 ,2,3,4-Tetrahydro-3-oxo-2-phenylmethyl-quinoxaline
To a solution of Compound B (720 mg, 2.34 mmol) in ethyl acetate (5 mL) at rt was added 20% Pd(OHyC (40 mg). The flask was filled with hydrogen gas via a balloon. After 5 hr, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The colorless solid was chromatographed (silica, flash, 30% EtOAc/hexanes) to afford Compund C (550 mg, 98%) as a solid. MS (M+H)+ 239.
D . 1 ,2,3,4-Tetrahydro-3-oxo-2-phenylmethyl-1 - (phenylmethyioxy-carbonyl)quinoxaline
To a solution of Compound C (525 mg, 2.2 mmol) in dichloromethane (6 mL) at 0°C were added DIEA (0.52 mL, 3 mmol) and benzylchloroformate. The mixture was allowed to warm to rt over 3 hr.
DMAP (10 mg) and pyridine (1 mL) were added and the mixture was stirred overnight (16 hr). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and 1N HCl (15 mL). The organic layer was separated, washed with 1 N HCl (15 mL), dried (MgS04), and concentrated in vacuo. The residue was chromatographed (silica, flash, 10% EtOAc/chloroform) to afford Compound D as a solid (440 mg, 54%). MS (M+H)+ 373.1.
E. 1 ,2,3,4-Tetrahydro-2-phenylmethyl-1-(phenylmethyloxy- carbonyl)quinoxaline
A mixture of Compound D (380 mg, 1.02 mmol) and borane in THF (1 M, 3 mL) was stirred at rt under argon. After 24 hr, MeOH (10 mL) was added carefully followed by 1 N HCl (1M in ether, 5 mL). After 1 hr, the mixture was concentrated in vacuo. The above procedure was repeated once more to afford a white solid which was then treated with chloroform and 10% ammonium hydroxide (20 mL each) and stirred vigorously. After 1 hr, the organic layer was separated, dried (MgS04), and concentrated in vacuo to afford Compound E as a solid (366 mg, 100%). MS (M+H)+ 359.1.
F. 1 ,2,3,4-Tetrahydro-7-bromo-2-phenylmethyl-1 -(phenyl- methyl-oxycarbonyl)quinoxaline
To a stirred solution of Compound E (340 mg, 0.95 mmol) in chloroform (3 mL) at rt was added a solution of tetrabutylammonium tribromide (457 mg, 0.95 mmol) in chloroform (2 mL) over 2 min. After 10 min, an aqueous solution of sodium bisulfite (10 mL) was added and the mixture was extracted with chloroform (10 mL). The organic layer was separated, dried (MgS04), and concentrated in vacuo. The residue was chromatographed (silica, flash, 15% EtOAc/hexanes) to afford Compound F (355 mg, 86%) as a thick oil. MS (M+H)+ 437, 439.
G. 1 ,2,3,4-Tetrahydro-7-bromo-4-[(1 H-imidazol-4-yl)methyl]- 2-phenylmethyM-(phenylmethyloxycarbonyl)quinoxaline, hydrochloride
To a solution of Compound F (345 mg, 0.79 mmol) in dichloromethane (3 mL) at rt were added 4-formylimidazole (0.3 g, 3.1 mmol), acetic acid (1 mL), 3A sieves and sodium triacetoxyborohydride (212 mg, 1 mmol). After 5hr, sodium borohydride (212 mg, 1 mmol) was added. After 15hr, the mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in chloroform (15 mL) and stirred vigorously with aqueous ammonia (15 mL). After 1 hr, the organic layer was separated, dried (MgSO„) and concentrated in vacuo. Chromatography (silica, flash, 10% i-PrOH in chloroform) afforded the free base (280 mg, 69%). 1 N HCl in ether (2 mL) was added to this solid (25 mg) and the mixture was dried in vacuo to afford Compound G (28 mg). MS (M+H)+ = 517, 519.
Example 414
Figure imgf000366_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4- (phenyl-sulfonyl)-3-(4-cyanophenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Example 414 was prepared as a solid in 12% yield from (R)-7- bromo-2,3,4,5-tetrahydro-3-(4-bromophenylmethyl)-1 H-1 ,4-benzodiazepine (prepared as described in Example 407) by the following sequence: Compound C of Example 248; Compound C of Example 224, using benzenesulfonyl chloride; Compound D of Example 224, with purification by reverse phase preparative HPLC (gradient of aq methanol with 0.1 % TFA). MS (M+H)+ 509, 13C NMR (CD30D, 100 MHz) 39.60, 47.69, 50.29, 55.65, 60.46, 102.42, 111.55, 116.13, 118.47, 119.87, 125.00, 128.22, 129.73, 132.14, 133.34, 133.48, 133.62, 135.32, 136.22, 141.24, 144.60, 152.53 ppm.
Example 415
Figure imgf000367_0001
(R)-7-Cyano-4-[(N-methyl-N-phenylmethyl)aminosulfonyl]-1-[(1 H- imidazol-4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 415 was prepared as a fluffy solid in 8% yield from N- methyl-N-phenylmethyl-suifamoyl chloride and Compound C of Example 248 by the following sequence: Compound A of Example 355, with reaction at 0°C to room temperature and chromatography with 20% ethyl acetate/hexanes; Compound C of Example 353, with reaction at reflux in the presence of 3A sieves. MS: [M+H]+ = 527.
Example 416
Figure imgf000368_0001
(R)-7-Cyano-4-[N-(tetrahydroisoquinolinyl)sulfonyl]-1-[(1 H- imidazol-4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 416 was prepared as a white solid in 11% yield from tetrahydroisoquinolinylsulfamoyl chloride and Compound C of Example 248 as described for Example 415. MS: [M+H]+ = 539.
Figure imgf000368_0002
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (phenylsulf onyl)-3-(2-thienylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
Example 417 was prepared as a yellow solid from 2- (thienyl)alanine and bromoisatoic anhydride as described for Example 407, using benzenesulfonyl chloride in place of methanesulfonyl chloride. MS (M+H)+ 490. Example 418
Figure imgf000369_0001
cis-2,3,4,5-Tetrahydro-1 ,5-bis(1 H-imidazol-4-ylmethyl)-3-
(phenyl-methyl)-1 H-1 ,5-benzodiazepine-2-carboxylic acid ethyl ester, trifluoroacetate (1 :2).
A. 2-Oxo-3-phenylmethyl-but-3-enoic acid, ethyl ester A solution of ethyl-2-oxo-4-phenylbutyrate (31.8 mmol, 6.0 mL),
N,N,N',N'-tetramethyldiaminomethane (6.6 mL, 54 mmol) and acetic anhydride (10 mL, 106 mmol) in DMF (100 mL) was stirred at room temperature for 16 hours and evaporated. The residue was chromatographed (flash silica, 20% EtOAc/Hexanes) to afford Compound A as a clear oil (6.46 g, 93%). MS (M+NH4)+ 236.
B. 2,3-Dihydro-3-(phenylmethyl)-1 H-1 ,5-benzodiazepine-2- carboxylic acid ethyl ester
A mixture of Compound A (6.46 g, 29.6 mmol), phenylenediamine (3.5 g, 32.6 mmol) and hydroquinone (300 mg, 2.72 mmol) in toluene (250 mL) was heated to reflux under Dean-Stark conditions for 6 hours. The mixture was concentrated and the residue was purified by flash chromatography (20% EtOAc/Hexanes) affording compound B as viscous yellow oil (3.3g, 36%). MS (M+H)+ 309.
C . cis-2,3,4,5-Tetrahydro-1 ,5-bis(1 H-imidazol-4-ylmethyl)-
3-(phenyl-methyl)-1 H-1 ,5-benzodiazepine-2-carboxylic acid ethyl ester, trifluoroacetate (1 :2) Compound B (165 mg, 0.76 mmol) was dissolved in 2 mL AcOH and 2 mL CH2CI2 and treated with 4-formylimidazole (183 mg, 1.9 mmol) and NaBH(OAc)3 (645 mg, 3.0 mmol). The mixture was stirred at room temperature for 16 hours, concentrated and partitioned between saturated NaHCOg (50 mL) and 10% isopropanol-CH2CI2. The organic phase was washed with saturated NaHCOg (50 mL), dried over Na2S04, dissolved in MeOH (2 mL) and purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) to afford a yellow oil (120 mg, 23%), which was lyophilized from water to yield Compound C as an off-white fluffy solid.
MS (M+H)+ 471.
Example 419
Figure imgf000370_0001
(R)-7-Cyano-4-[(N-piperidinyl)sulfonyl]-1 -[(1 H-imidazol-4- y l)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
Example 419 was prepared as a fluffy white solid in 26% yield from
N-piperidinylsulfamoyl chloride and Compound C of Example 248 as described for Example 415, with the final chromatography using 5% methanol/chloroform. MS (M+H)+ = 491.
Figure imgf000371_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-1-methyl-imidazol-5- ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
A mixture of Compound A of Example 284 (150 mg, 0.366 mmol), 1-methyl-5-formylimidazole (121 mg, 1.10 mmol) and 200 mg of 3A molecular sieves in 2 mL of 3:1 DCE/AcOH was heated at 60°C. At 1 hr, 4 hr, 7 hr and 10 hr, aliquots of sodium triacetoxyborohydride (116 mg, 0.549 mmol) were added. At 3 hr, 6 hr and 9 hr, aliquots of aldehyde (91 mg, 0.946 mmol) were added. Acetic acid (1 mL) was also added at 9 hr. Following the last addition of hydride, the mixture was stirred at 60°C for 2 hr diluted with 5 mL of methanol, filtered, and concentrated in vacuo. The residue was diluted with 100 mL of EtOAc and washed with 1 N NaOH (3 x 50 mL), and brine. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and the appropriate fractions were concentrated. The residue was dissolved in 1 M HCl (3 x 5 mL) and concentrated in vacuo. The residue was dissolved in minimal acetonitrile, diluted with water and freeze-dried to provide 60 mg (29%) of Example 420 as a white solid. (M+H)+ 504.
Analysis calculated for C26H25N502S2 • 1.50 HCl • 0.66 H20.
Calc'd: C, 54.77; H, 4.92; N, 12.28.
Found: C, 54.77; H, 4.92; N, 12.25.
Figure imgf000372_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (pyridin-3-ylmethyl)-4-[[2-(dimethylamino)ethyl]sulfonyl]-1 H-1 ,4- benzodiazepine, trihydrochloride.
A. (R)-7-Cyano-2,3,4,5-tetrahydro-3-(pyridin-3-ylmethyl)-4-
[[2-(dimethylamino)ethyi]sulfonyl]-1 H-1 ,4-benzodiazepine
2-Chloroethane sulfonyl chloride (0.79 ml, 7.6 mmol) was added to a solution of Compound B of Example 350 (1.0 g, 3.8 mmol) and DIEA (0.66 ml, 3.8 mmol) in CH2CI2 at -78°C. The mixture was stirred at -78°C for 15 minutes. DIEA (0.66 ml, 3.8 mmol) was added and the mixture was stirred at -78°C for 1h. DIEA (2.6 ml, 15.2 mmol) was again added to the reaction mixture at -78°C. The mixture was allowed to warm to room temperature and stirring was continued for 16h. The solution was concentrated under vacuum. The residue was dissolved in 3/1 THF/CH2CI2 (4 ml). The mixture was saturated with dimethylamine, condensed using a dry-ice cold finger at room temperature. The mixture was stirred at room temperature for 2h. The resulting solution was diluted with 10% NaHCOg (100 ml) and the solution was extracted with 9/1 CKjClj iPrOH (3X150 ml). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum to afford Compound A (1.5g, 100%). MS: (M+H)+ 400 B. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(pyridin-3-ylmethyl)-4-[[2- (dimethylamino)ethyl]sulfonyl]-1 H-1 ,4-benzo-diazepine, trihydrochloride 4-Formylimidazole (0.14 g, 1.5 mmol) was added to a solution of 1
(0.30 g, 0.75 mmol) and 3A molecular sieves in 1/1 DCE: acetic acid (5 ml) and the mixture was stirred at 70°C for 0.5h. Sodium triacetoxyborohydride (0.32 g, 1.5 mmol) was added and the mixture was stirred at 70°C for 15 minutes. 4-Formylimidazole (0.14 g, 1.5 mmol) was added and the mixture was stirred at 70°C for 0.5h. Sodium triacetoxyborohydride (0.32 g, 1.5 mmol) was added and the mixture was stirred at 70°C for 15 minutes. The latter two steps were repeated four times. The mixture was cooled to room temperature, diluted with methylene chloride (30 ml), filtered and the filtrate concentrated under vacuum. The residue was diluted with 25% NH4OH (50 ml) and the solution was extracted with 9/1 CHjClj iPrOH (4X50 ml). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by reverse phase preparative HPLC (gradient of aq MeOH with 0.1% TFA) and the appropriate fractions were isolated and concentrated under vacuum. The residue was evaporated from 1/1 CH3OH/1 N HCl (2 ml) 5X. The residue was dissolved in CHgCN (2 ml) and 1 N HCl (4 ml) and lyophilized to afford Compound B (0.071 g, 16 %) as a solid. MS: (M+H)+480 Analysis calculated for C24H29N702S • 3.3 HCl • 0.74 H20. Calc'd: C, 47.01 ; H, 5.55; N, 15.99; S, 5.23; Cl, 19.08. Found: C, 47.00; H, 5.43; N, 15.53; S, 5.00; Cl, 18.98.
Figure imgf000374_0001
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-1-methyl-imidazol-5- ylmethy l)-3-(phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
A solution of 320 mg (0.87 mmol) of Compound A of Example 317 in 5 mL of dichloroethane and 500 mL of glacial acetic acid was treated with 478 mg (4.34 mmol) of 1-methyl-imidazole-5-carboxaldehyde and 3A sieves. The mixture was heated to 60°C, stirred for 5 hrs and treated with 763 mg (3.60 mmol) of sodium triacetoxyborohydride. The mixture was allowed to cool to rt, stirred for 18 hrs and filtered. The filtrate was concentrated in vacuo. The residue was partitioned between 150 mL of 1N sodium hydroxide and 150 mL of ethyl acetate. The organic layer was washed with brine, dried (Na2S04), filtered and concentrated in vacuo. The brown oil was purified by reverse phase preparative HPLC (gradient of aq methanol with 0.1% TFA). The resulting white foam was evaporated 3X from methanolic hydrogen chloride. The white foam was dissolved in water and lyophilyzed to afford Example 422 (59 mg, 15%) as a white lyophilate. MS: (M+H)+ = 464+
Example 423
Figure imgf000375_0001
N-(Cyano)-N'-methyl-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4 ylmethyl)-7-phenyl-4H-1 ,4-benzodiazepine-4-imidamide, hydrochloride.
A. N-(Cyano)-O-phenyl-1 ,2,3,5-tetrahydro-7-phenyl-4H-1 ,4- benzodiazepine-4-imidate A solution of 500 mg (1.58 mmol) of Compound B of Example 224 in 20 mL of DMF was treated, under argon, with 390 mg (1.64 mmol) of diphenyl cyanocarbonimidate followed by 275 μL (1.58 mmol) of DIEA and 97 mg (0.79 mmol) of DMAP. The mixture was stirred at rt for 15 min, at 80°C for 3.5 hrs and at rt for 80 hrs. The mixture was partitioned between 250 mL of ethyl acetate and 250 mL of 1 N sodium hydroxide. The aqueous layer was extracted 3x with 100 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated in vacuo. The oil was purified by flash chromatography (silica, 40% ethyl acetate/hexane) to give 456 mg (63%) of Compound A as a white solid.
B. N-(Cyano)-N'-methyl-1 ,2,3,5-tetrahydro-7-phenyl-4H-1 ,4- benzodiazepine-4-imidamide
A solution of 180 mg (0.39 mmol) of Compound A in 1mL of DMF was treated with 242 μL (1.94 mmol) of a solution of 33% methylamine in ethanol. The mixture was stirred at rt for 1hr and concentrated. The residue was dissolved in 100 mL of ethyl acetate, washed with brine, dried (Na2S04) and concentrated in vacuo to give 125 mg (87%) of Compound B as a white solid. MS (M+H)+ = 400. C. N-(Cyano)-N'-methyl-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-
4-ylmethyl)-7-phenyl-4H-1 ,4-benzodiazepine-4-imidamide, hydrochloride
A solution of 115 mg (0.29 mmol) of Compound B in 2.5 mL of dichloroethane and 2.5 mL of glacial acetic acid was treated with 69 mg (0.71 mmol) of 4-imidazole-carboxaldehyde, 3A sieves and stirred at rt for 18hrs. The mixture was treated with 122 mg (0.58 mmol) of sodium triacetoxyborohydride in one portion and stirred at rt for 30min and filtered. The filtrate was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N sodium hydroxide. The organic layer was washed with brine, dried (Na2S04), and concentrated in vacuo. The oil was purified by reverse phase preparative HPLC (gradient of aq methanol with 0.1% TFA). The yellow foam was evaporated 3X from methanolic hydrogen chloride. The foam was dissolved in water and lyophilyzed to afford 30 mg (22%) of Compound C as a yellow lyophilate. MS: (M+H)+ = 480.
Example 424-430
Examples 424-430 were prepared from Compound C of Example 248 and the appropriate sulfonyl chloride as described by the following sequence: Compound A of Example 299; Compound B of Example 317. Satisfactory C, H and N analyses were obtained for Examples 424-430.
Example Mass
Spectrum
424 (R)-7-Cyano-4-[(2- m/z nitrophenyl)-sulfonyl]- 529 2,3,4,5-tetrahydro-1-(1 H- (M+H) imidazol-4-ylmethyl)-3- (phenyl-methyl)-l H-1 ,4- benzodiazepine, hydrochloride.
Figure imgf000376_0001
(R)-7-Cyano-4-[(4-methyl- m/z phenyl)sulfonyl]-2,3,4,5- 498 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepine, hydrochloride.
(R)-7-Cyano-4- m/z
(butylsulfonyl)-2,3,4,5- 464 tetrahydro-1 -(1 H-imidazol-4- (M+H) ylmethyl)-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepine, hydrochloride.
(R)-7-Cyano-4-[(2-trifluoro- m/z methylphenyl)sulfonyl]- 552
2,3,4,5-tetrahydro-1-(1 H- (M+H) imidazol-4-ylmethyl)-3- (phenylmethyl)-1H-1 ,4- benzodiazepine, hydrochloride.
(R)-7-Cyano-4-[(2- m/z trifluoromethoxyphenyl)sulfo 568 nyl]-2,3,4,5-tetrahydro-1- (M+H) (1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Figure imgf000377_0001
429 (R)-7-Cyano-4-[(2-methoxy- m/z carbonylphenyl)sulfonyl]- 568 2,3,4,5-tetrahydro-1-(1H- (M+H) imidazol-4-ylmethyl)-3- (phenylmethyl)-1H-1 ,4- benzodiazepine, hydrochloride.
430 (R)-7-Cyano-4-[(2-methyl- m/z sulfonylphenyl)sulfonyl]- 562 2,3,4,5-tetrahydro-1-(1H- (M+H) imidazol-4-ylmethyl)-3- (phenylmethyl)-1 H-1 ,4- benzodiazepine, hydrochloride.
Figure imgf000378_0001
Example 431
The following examples were prepared using the methods described herein as well as by methods known to those skilled in the art.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- m/z 562 ylmethyl)-3-(phenylmethyl)-4-(((4-methylsulfonyl)- (M+H) phenyl)-sulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- m/z 552 ylmethyl)-3-(phenylmethyl)-4-(((4-trifluoromethyl)- (M+H) phenyl)-sulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- m/z 480 ylmethyl)-3-(phenylmethyl)-4-((3-methoxypropyl)- (M+H) sulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- m/z 544 ylmethyl)-3-(phenylmethyl)-4-((3,4-dimethoxyphenyl)- (M+H) sulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- m/z 502 ylmethyl)-3-((4-fluorophenyl)methyl)-4- (M+H) (phenylsulfonyl)-l H-1 ,4-benzodiazepine
(R)-7-Cyano-4-[(N-cyclopropylmethyl-N-propyl)- m/z 519 aminosulfonyl]-1 -[(1 H-imidazol-4-yl)methyl]-3- (M+H) (phenylmethyl)-l H-1 ,4-benzodiazepine
(R)-7-Cyano-4-[(N,N-(dibutylamino))-sulfonyl]-1 -[(1 H- m/z 535 imidazol-4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4- (M+H) benzodiazepine
(R)-7-Chloro-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1- m/z 432
(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H- (M+H) pyrido[3,4-e]-1 ,4-diazepine
1 ,2,3,4-Tetrahydro-7-bromo-4-[(1 H-imidazol-4- m/z 460 yl)methyl]-2-phenylmethyl-1 - (M+H) (methylsulfonyl)quinoxaline
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- m/z 424 ylmethyl)-3-(phenylmethyl)-4-((imidazol-4- (M+H) yl)methylsulfonyl)-1 H-1 ,4-benzodiazepine
Following the above procedures, the following compounds may be made: (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-((2- thienyl)methyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-((2- thienyl)methyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((3-methylthiopropyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(((3-methylthioxo)-propyl)-sulfonyl)-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(((3-methylsulfonyl)-propyl)-sulfonyl)-1H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((2-methylpropyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(cyclopentylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((4,4,4-trifluorobutyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((phenylmethyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[[2-(5-(N-benzoyl)-aminomethyl)-thienyl]-sulfonyl]-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[[2-(1 -(3-chloro-5-methyl-pyridin-2-yl))-pyrrolyl]-sulfonyl]-
1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((4-carboxyphenyl)-sulfonyl)-1H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[((3-methyl-1 ,2,4-oxadiazol-5-yl)-phenyl)-sulfonyl]-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((2,5-dimethoxyphenyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N-tetrahydroquinolinyl)sulfonylJ-
1 -[(1 H-imidazol-4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N,N-bis-[1 -(2-methylpropyl)amino]-sulfonyl]-1 -[(1 H-imidazol- 4-yl)methylj-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N-methyl-N-phenyl)aminosulfonyl]-1-[(1 H-imidazol-4- yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(2-(2,6- dimethylphenyl)-ethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1-(N-phthalimidoethyl)-imidazol-5- ylmethyl)-3-(phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-[(2-(N,N-dimethylamino)-ethyl)-imidazol-5- ylmethyl]-3-(phenylmethyl)-4-(methylsulfonyl)- 1 H- 1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-[(2-aminoethyl)-imidazol-5-ylmethyl]-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Bromo-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-thieno[2,3-e]-1 ,4-diazepine (R)-7-Bromo-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-thieno[3,2-e]-1 ,4-diazepine (R)-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-8-oxo-pyrimidino[4,5-e]-1 ,4-diazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-((4-(2- methoxyethoxy)-phenyl)methyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-((4-(2- (dimethylamino)-ethoxy)-phenyl)methyl)-4-(phenylsulfonyl)-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylsulfonyl)-3-
(phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(R)-1 -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)-1 -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)-1 -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(R)- -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(S)-[(R)- -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-3-(R)-[(S)- -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(S)-[(S)- -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[(2-(5-(pyridin-2-yl))-thienyl)-sulfonyl])-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[(2-(5-(1 ,2-isoxazol-3-yl))-thienyl)-sulfonyl])-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(2-(1 H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(2-(1H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(2-(1 H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(2-(1 H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((1 -oxoethyl)-amino)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(methanesulfonylamino)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(phenylsulfonylamino)-1 H-1 ,4-benzodiazepine

Claims

What is claimed:
1. A compound of the formula
Figure imgf000385_0001
their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit farnesyl protein transferase which is an enzyme involved in ras oncogene expression. In formulas l-IV and throughout their specification, the above symbols are defined as follows: m, n, r, s and t are 0 or 1 ; p is 0, 1 or 2; V, W and X are selected from the group consisting of oxygen, hydrogen, R1 , R2 or R3; Z and Y are selected from the group consisting of CHR9, S02, SO , CO,
Cθ2, O, NR10, SO2NR1 1 , CONR12,
N-CN N-CN O
II II II
— C — / — C -N — / — N-C— / — N-SOp- I I I
R13 R14 R15
O
— C -N-N— / -S02-N-N— / %J^R2° R21^ NR22
R16R17 R18R19 — S— / - — / or Z may be absent;
R6, R7, R9, R10, R1 1 , R12, R13, R14, R15, R 6, R17, R18, R19 R2° , R21 , R22, R24, R25, R26, R27, R28, R29, R30 , R31 , R32 R33, R 34, R3*, R38 R37, and R38 are selected from the group consisting of hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl; R , R5 are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R23;
U is selected from the group consisting of sulfur, oxygen, NR24, CO, SO, S02, C02, NR25C02 , NR26CONR27, NR28S02, NR29SO2NR30,
S02NR31 , NR32CO, CONR33, PO2R34 and PO3R35 or U is absent; R , R , and R3 are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. CONH2) or substituted carbamyl further selected from CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl;
R8 and R23 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo; Any two of R1 , R2, and R3 can be joined to form a cycloalkyl group; R, S and T are selected from the group consisting of CH2, CO and
CH(CH2)pQ wherein Q is NR36R37 OR38, or CN; and
A, B, C and D are carbon, oxygen, sulfur or nitrogen, with the provisos that 1. When m is zero then V and W are not both oxygen or
2. W and X together can be oxygen only if Z is either absent, O, NR10, o
II
— N -C — / or — N -S02—
CHR9, 14 R15 in formulas I and II, and V and X together can be oxygen only if Y is O, NR10, O
II
— N -C — / or — N -S02-
CHR9, R 4 R15 in formulas III and IV or
3. R23 may be hydrogen except when U is SO, S0 , NR25C02 or
NR28SO2 , or
4. R8 may be hydrogen except when Z is S02, C0 , or
O. NR20 R21N NR22
— -S02— / — S — / — s — R15
2. The compound of claim 1 wherein the compound is selected from the group consisting of
Figure imgf000388_0001
3. The compound of claim 2 wherein m is zero and ABCD is a carbocyclic ring.
4. The compound of claim 3 wherein the carbocyclic ring is benzo.
5. The compound of claim 1 wherein the compound is of the formula
Figure imgf000388_0002
wherein m is zero and ABCD is a carbocyclic ring.
6. The compound of claim 5 wherein the carbocyclic ring is benzo.
7. A compound of claim 1 selected from the group consisting of: 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepine, hydrochloride; 8-Chloro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride;
1 ,2,3,4-tetrahydro-4-[(3H-imidazol-4-yl) methyl]-1 -(naphthalen-1 - ylcarbonyl)quinoxaline, dihydrochloride;
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-yl-methyl)-1 -(1 -1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-2-methyl-4-(1 - naphthalenylcarbonyl)-1-H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-4-(1-naphthalenylcarbonyl)-1 -[[1-(phenylmethyl)-1 H- imidazol-5-yl]methyl]-1 H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-(1 H-imidazol-4-yl-methyl)-4-(1 -naphthalenylsulfonyl)-1 H- 1 ,4-benzodiazepine, hydrochloride;
(S)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-[2-(methylthio)ethyl]-4-
(1-naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-yl-methyl)-N-methyl-N-phenyl-4H-1 ,4- benzodiazepine-4-carboxamide, hydrochloride; 2-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-yl-methyl)-1 H-1 ,4-benzodiazepin-4- yl]sulfonyl]benzoic acid, methyl ester, hydrochloride;
7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-2-ylmethyl)-4-(1-naphthalenylcarbonyl)-
1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -[3-(1 H-imidazol-2-yl)propyl]-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 1 -[3-Amino-3-(1 H-imidazol-2-yl)propyl]-2,3,4,5-tetrahydro-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-methyl-4-(1 - napthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, hydrochloride;
(S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[2-(methylthio)ethyl]-4-
(1 -naphthalenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-9-methyl-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-9-methyl-1 -(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihyrdochloride;
1 -[[2-(2-Aminoethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
1 -[[2-Aminomethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]acetamide, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
1 H-pyrido[2,3-e]-1 ,4-diazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
1 H-naphtho[2,3-e]-1 ,4-diazepine, dihydrochloride; 2,3,4, 5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(1-naphthalenylcarbonyl)-
8-nitro-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
8-amino-1 H-1 ,4-benzodiazepine, dihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]benzamide, dihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]cyclohexanamide, dihydrochloride; 2,3,4,5-Tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethyl]-4-(1 -naphthalenylcarbonyl)-
1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethyl]-4-(1 -naphthalenylcarbonyl)-
7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
7-Bromo-2,3,4,5-tetrahydro-1 -[2-(1 H-imidazol-4-yl)ethyl]-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
1 -[[1 -(2-Aminoethyl)-1 H-imidazol-5-yl]methyl]-2,3,4,5-tetrahydro-4-(1 - naphthaienylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine-4-carboxylic acid, phenylmethyl ester;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[2-
(trifluoromethoxy)benzoyl]-1 H-1 ,4-benzodiazepine; 1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N-methyl-N,7-diphenyl-4H-
1 ,4-benzodiazepine-4-carboxamide, dihydrochloride;
2,3,4,5,-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthaleneylcarbonyl)-
7-(1 -piperidinylsulfonyl)- 1 H-1 ,4-benzodiazepine, monohydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)- 7-pyridin-2-yl-1 H-1 ,4-benzodiazepine, trihydrochloride;
7-(2-Furanyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4, 5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
7-(2-thienyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(1-naphthalenylcarbonyl)-
7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -[3-(1 H-imidazol-2-yl)propyl]-4-(1 - naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
7-Bromo-2,3,4,5-tetrahydro-4-(1 H-imidazol-4-ylmethyl)-1 -(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
8-Chloro-2,3,4,5-tetrahydro-4-(1 H-imidazol-4-ylmethyl)-1 -(1 - naphthalenylcarbonyl)-1 H-1 ,4-beπzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-1 -(1 -naphthalenylcarbonyl)-
7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride; 2,3,4,5-Tetrahydro-1 ,4-bis(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, trifluoroacetate;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-methoxy-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4, 5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
1 H-1 ,4-benzodiazepine-7-carboxylic acid, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-5-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
7-cyclohexyl-1 H-1 ,4-benzodiazepine, 2.5 hydrochloride; 7-Butyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 1 -[[2-(2-Aminoethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro-4-(1- naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
1-[[2-(Aminomethyl)-1 H-imidazol-4-yl]methyl]-2,3,4,5-tetrahydro-4-(1- naphthalenylcarbonyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
8-[N,N-bis(phenyl-methyl)amino]-1 H-1 ,4-benzodiazepine, trihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-4-(1 - naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepin-8- yl]phenylsulfonamide,dihydrochloride; N-Phenyl-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-yl-methyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzo-diazepine-7-carboxamide, dihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-3-methylbenzamide, dihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-4-methylbenzamide, dihydrochloride;
3-Chloro-N-[2,3,4,5-tetrahydro-1-(1 H-imidazol-4-yl-methyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzo-diazepin-8-yl]benzamide, dihydrochloride;
7-Bromo-2,3,4,5,-tetrahydro-1-[[2-[(dimethylamino)-methyl]-1 H-imidazol-4- yl]methyl]-4-(1 -naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 7-(4-Chlorophenyl)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 7-(3-Aminophenyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride; 1 -Methyl-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-1 H-pyrrole-2- carboxamide, trihydrochloride; N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-3-furancarboxamide, dihydrochloride; 7-(3-Chlorophenyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride; 2-Methyl-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]benzamide, dihydrochloride;
N-Phenyl-N'-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]urea, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
7-(3-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-9-methoxy-4-(1 - naphthalenylcarbonyl)-1H-1 ,4-diazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)-
7-phenyl-1 H-pyrido[2,3-e]-1 ,4-diazepine, trihydrochloride;
(R)-2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-[2-(methylthio)ethyl]-4-
(1 -naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)- 3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride;
2,3,4,5-Tetrahydro-3-(2-hydroxyethyl)-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepine, trifluoroacetate;
2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-3-[2-(methylthio)ethyl]-4-(1- naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate; (S)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1- naphthalenylcarbonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate;
4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride; 2,3,4,5-Tetrahydro-4-(1 H-imidazol-4-ylmethyl)-1-(1-naphthalenylcarbonyl)-
3-(phenylmethyl)-1H-1 ,4-benzodiazepine, 1.5 hydrochloride;
7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
4H-1 ,4-benzodiazepine-4-carboxamide, trifluoroacetate;
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3- (phenylmethyl)-1H-1 ,4-benzodiazepine, hydrochloride;
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine, trifluoroacetate;
4-Acetyl-7-bromo-3-[(4-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-1H-1 ,4-benzodiazepine, dihydrochloride; 4-Acetyl-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H- naphtho[2,3-e]-1 ,4-diazepine, monohydrochloride; N-Cyclohexyl-N'-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl)urea, dihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-l H-naphtho[2,3-e]-1 ,4-diazepine, monohydrochloride; 2,2-Dimethyl-N-[2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]propanamide, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylsulfonyl)-7- phenyl-1 H-1 ,4-benzodiazepine, monohydrochloride; 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(2- naphthalenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(1 - naphthalenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
7-(2-Chlorophenyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, monohydrochloride;
1 -Methyl-N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-2- piperidinecarboxamide, trihydrochloride;
N-[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-4- morpholinecarboxamide, dihydrochloride;
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepin-8-yl]-3-methylbutanamide, dihydrochloride;
1 ,2,3,4-Tetrahydro-4-[(1 H-imidazol-4-yl) methyl]-1-(naphthalen-1 - ylsulfonyl)quinoxaline, dihydrochloride;
1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N,7-triphenyl-4H-1 ,4- benzodiazepine-4-carboxamide, dihydrochloride;
1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H- naphtho[2,3-e]-1 ,4-diazepine-4-carboxylic acid, methyl ester, monohydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(4-phenyl-1 ,2,3- thiadiazol-5-yl)carbonyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate; 8-[[(Cyclohexylamino)carbonyl]amino]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-4-carboxylic acid,1 ,1 - dimethylethyl ester;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-8-[[(4- methylphenyl)sulfonyl]amino]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-4- carboxylic acid, 1 ,1-dimethylethylester;
7-Bromo-1 ,2,3,4-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
5H-1 ,4-benzodiazepin-5-one, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[1 -oxo-3-(1 - piperidinyl)propyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(4- quinolinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
4-[(5-Bromo-3-pyridinyl)carbonyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; (S)-4-[2-(Dimethylamino)-1-oxo-3-phenylpropyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-4-[4-hydroxy-3-(4-mo holinyl-methyl)benzoyl]-1-(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
(S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 -methyl-2- pyrrolidinyl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1H-imidazol-4-ylmethyl)-7-phenyl-4-[[2-(propylthio)-3- pyridinyl]carbonyl]-1 H-1 ,4-benzodiazepine, trihydrochloride;
4-[(2-Chloro-6-methyl-4-pyridinyl)carbonyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[[2-(phenylthio)-3- pyridinyl]carbonyl]-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[[2-(4-methylphenoxy)-3- pyridinyl]carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2-methoxy-3- pyridinyl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(5-phenyl-4- oxazolyl)carbonyl]-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-Acetyl-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(tetrahydro-3- furanyl)carbonyl]-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(2-methoxyethoxy)acetyl]-
7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[4-(4- morpholinylmethyl)benzoyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[4-(methylsulfonyl)benzoyl]-
7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[1 -oxo-3-
(phenylsulfonyl)propyl]-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(3- pyridinylacetyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(2- quinoxalinylcarbonyl)-1 H-1 ,4-benzodiazepine, tetrahydrochloride;
2,3,4, 5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(4-isoquinolinylcarbonyl)-7- phenyl-H-1 ,4-benzodiazepine, trihydrochloride;
4-[(2-Chloro-3-pyridinyl)carbonyl]-2,3,4,5-tetrahydro-1 -(1H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(3- pyridinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride; 4-[(2,6-Dimethoxy-3-pyridinyl)carbonyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(2- pyrazinylcarbonyl)-1 H-1 ,4-benzodiazepine, tetrahydrochloride;
4-(2-Ethoxybenzoyl)-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-7-phenyl- 1H-1 ,4-benzodiazepine, dihydrochloride;
4-[3-(Dimethylamino)benzoyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-
7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(1 - phenylcyclopropyl)carbonyl]-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-[(Bicyclo[4.2.0]octa-1 ,3,5-trien-7-yl)carbonyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-Benzoyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepine, dihydrochloride;
4-(2-Chlorobenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl- 1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2,3-Dichlorobenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; N-[2-[[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepin-4-yl]carbonyl]phenyl]-acetamide, dihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(2-phenoxybenzoyl)-7- pheny!-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-methoxybenzoyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2,3-Dimethoxybenzoyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2,4-Dimethoxybenzoyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2,5-Dimethoxybenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2,6-Dimethoxybenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-(2,3-Dihydroxybenzoyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-([1 ,1 '-Biphenyl]-2-ylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-methylbenzoyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2,3-Dimethylbenzoyl)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(3-Cyanobenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride; 4-(3-Chlorobenzoyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(3-phenoxybenzoyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(3-methoxybenzoyl)-7- phenyl-1 H-1,4-benzodiazepine, dihydrochloride;
4-(3,4-Dimethoxybenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(3,5-Dimethoxybenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(3-methylbenzoyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-(1 ,2-Dioxo-2-phenylethyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1H-1 ,4-benzodiazepine, dihydrochloride;
4-[(2-Ethoxy-1 -naphthalenyl)carbonyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-naphthalenylcarbonyl)-
7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(Fluorophenylacetyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(Diphenylacetyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl- 1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-4-(2-hydroxy-1-oxo-2-phenylpropyl)-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 H-indol-2-ylcarbonyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 H-indol-3-ylcarbonyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 H-indol-5-ylcarbonyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 -methyl- 1 H-indol-2- yl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-(2-Benzofuranylcarbonyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(3- pyridinylcarbonyl)-1 H-1 ,4-benzodiazepine, N-oxide, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(2- pyridinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(2- quinolinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(1 - isoquinolinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
4-(3-Chloro-2-nitrobenzoyl)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(2-nitrobenzoyl)-7-phenyl- 1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(3-methoxy-2-nitrobenzoyl)- 7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 H-indol-4-ylcarbonyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-[(2,6-Dihydroxy-3-naphthalenyl)carbonyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-(1 H-Benzimidazol-5-ylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; 4-(1 H-Benzotriazol-5-ylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4, 5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(4-methoxy-2- quinolinyl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; N-[3-[[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepin-4-yl]carbonyl]phenyl]-acetamide, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-methyl-1 -oxo-2- phenylpropyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-[2-(Dimethylamino)benzoyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
4-(3-Ethoxybenzoyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl- 1 H-1 ,4-benzodiazepine,dihydrochloride; 2,3,4,5-Tetrahydro-4-(2-hydroxy[1 ,1 '-biphenyl]-3-ylcarbonyl)-1 -(1 H-imidazol- 4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-4-[2-[(2-hydroxyethyl)thio]benzoyl]-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2-methoxy-1 - naphthalenyl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-4-[(2-hydroxy-4-quinolinyl)-carbonyl]-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2-[[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4- benzodiazepin-4-yl]carbonyl]benzamide,dihydrochloride; N-(1 ,1-Dimethylethyl)-2-[[2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepin-4-yl]carbonyl]benzamide, dihydrochloride; N-(4-Fluorophenyl)-N'-[3-[[2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-1 H-1 ,4-benzodiazepin-4-yl]carbonyl]phenyl]urea, dihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(3-methyl-4-oxo-2-phenyl- 4H-benzopyran-8-yl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[3- (trifluoromethoxy)benzoyl]-1 H-1 ,4-benzodiazepine, dihydrochloride; 4-(2-Cyanobenzoyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-[[(4- methyiphenyl)sulfonyl]amino]benzoyl]-7-phenyl-1H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(6- quinolinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(8- quinolinylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride; 4-(Benzo[b]thiophen-2-ylcarbonyl)-2,3,4,5-tetrahydro-1-(1H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
4-[[4-(Dimethylamino)-1-naphthalenyl]carbonyl]-2,3,4,5-tetrahydro-1-(1H- imidazol-4-ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(1 H-purin-6- ylcarbonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4, 5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methoxyphenylacetyl)-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(5-methyl-1-phenyl-1H- pyrazol-4-yl)carbonyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-(2-methylphenyl)-1 - oxopropyl]-7-phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(tetrahydro-4- phenyl-2H-pyran-4-yl)carbonyl]-1 H-1 ,4-benzodiazepine, dihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2- (methylphenylamino)benzoyl]-7-phenyl-1 H-1 ,4-benzodiazepine, trihydrochloride;
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(4- quinolinylcarbonyl)-1 H-1 ,4-benzodiazepine, N-oxide, dihydrochloride; N- ethyl-N-(2-pyridinylmethyl)-2-[[2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepin-4-yl]carbonyl]benzamide, trihydrochloride;
2,3,4, 5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(3-isoquinolinylcarbonyl)-7- phenyl-1H-1 ,4-benzodiazepine, trihydrochloride; 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2- naphthalenylthio)acetyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
4-[3-(3,4-Dimethoxyphenyl)-1 -oxopropyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol- 4-ylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2); 4-([1 , 1 '-Biphenyl]-4-ylacetyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-
1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-naphthalenylacetyl)-1 H-
1 ,4-benzodiazepine,trifluoroacetate (1 :2); 4-([1 ,1'-Biphenyl]-2-ylcarbonyl)-2,3,4T5-tetrahydro-1-(1H-imidazol-4- ylmethyl)-1H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2-phenyl-4- quinolinyl)carbonyl]-1H-1 ,4-benzodiazepine, trifluoroacetate (1:3);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(3-pyridinylacetyl)-1 H-1 ,4- benzodiazepine, trifluoroacetate (1 :3);
4-(9H-Fluoren-9-ylacetyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-1 H-
1 ,4-benzodiazepine, trifluoroacetate (1 :2);
(S)-4-[2-(Dimethylamino)-1 -oxo-3-phenylpropyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :3); (S)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2-oxo-4-phenyl-3- oxazolidinyl)acetyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
4-(9-Acridinylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-1 H-
1 ,4-benzodiazepine, trifluoroacetate (1 :3);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(3-phenoxybenzoyl)-1 H- 1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[[4'-(trifluoromethyl)[1 , 1 '- biphenyl]-2-yl]carbonyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(4-phenoxybenzoyl)-1 H-
1 ,4-benzodiazepine, trifluoroacetate (1 :2); 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-naphthalenylcarbonyl)-
1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1 -oxo-4-phenylbutyl)-1 H-
1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2-phenoxyphenyl)acetyl]- 1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-[(4- methylphenyl)sulfinyl]benzoyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-
[(phenylmethyl)amino]benzoyl]-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :3);
1 ,2,3,5-Tetrahydro-1-(1 H-imidazol-4-yl-methyl)-N,N-diphenyl-4H-1 ,4- benzodiazepine-4-carboxamide, hydrochloride; 1 ,2,3,5-Tetrahydro-1 -(1 H-imidazol-4-yl-methyl)-a,7-diphenyl-4H-1 ,4- benzodiazepine-4-acetic acid, methyl ester, hydrochloride;
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-
1 ,4-benzodiazepine, hydrochloride; (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride;
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile, monohydrochloride;
(R)-4-Acetyl-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-phenyl-3- (phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride;
7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine, trifluoroacetate (1 :2);
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4-[(1 ,2,3,4- tetrahydro-1-quinolinyl)carbonyl]-1 H-1 ,4-benzodiazepine, monohydrochloride;
N-Ethyl-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-N,7-diphenyl-4H-1 ,4- benzodiazepine-4-carboxamide, monohydrochloride;
4-[(2,3-Dihydro-1 H-indol-1 -yl)carbonyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, monohydrochloride;
2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride;
(R)-4-[[2-(Dimethylamino)ethyl]sulfonyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1:1);
[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1 -naphthalenylcarbonyl)- 1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, cyclohexyl ester, dihydrochloride; (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 -methyl-1 H-imidazol-5-yl)methyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride; (R)-7-Cyano-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-7- phenyl-3-(phenylmethyl)-1 H-pyrido[3,2-e]-1 ,4-diazepine, monohydrochloride.
4-[2-(4-Chlorophenyl)-1 ,2-dioxoethyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride. 4-(1 ,2-Dioxopropyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzodiazepine, hydrochloride.
2,3,4, 5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-(4-nitrophenyl)-1 ,2- dioxoethyl]-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[2-(4-methoxyphenyl)-1 ,2- dioxoethyl]-7-phenyl-1 H-1 ,4-benzodiazepine, hydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(3,3,3-trifluoro-
1 ,2-dioxopropyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :2).
(R)-7-Chloro-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4-yl)-methyl]-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-pyrido[3,2-e]-1 ,4-diazepiπe, hydrochloride.
6,7,8,9-Tetrahydro-5-(1H-imidazol-4-ylmethyl)-8-(1-naphthalenylcarbonyl)-
2-phenyl-5H-pyrimido-[5,4-e][1 ,4]diazepine, monohydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylacetyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(2-1 H-imidazol-4-ylethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. 8-[(Cyclohexylcarbonyl)amino]-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, methyl ester, dihydrochloride.
N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepin-8-yl]-1 - piperidinecarboxamide, dihydrochloride.
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, ethyl ester, hydrochloride. N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepin-8-yl]cyclohexanecarboxamide, dihydrochloride.
(R)-7-Cyano-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[[2-(4- morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-4H-1 ,4-benzodiazepine, dihydrochloride. N-[2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(2-methoxy-3- methylbenzoyl)-1 H-1 ,4-benzodiazepin-8-yl]cyclohexanecarboxamide, dihydrochloride.
8-[(Cyclohexylcarbonyl)amino]-2,3,4,5-tetrahydro-1-(1H-imidazol-4- ylmethyl)-N-phenyl-1 H-1 ,4-benzodiazepine-4-carboxamide, dihydrochloride.
N-[2,3,4,5-Tetrahydro- 1 -( 1 H-imidazol-4-ylmethyl)-4-[(2- methylphenyl)sulfonyl]-1 H-1 ,4-benzodiazepin-8-yl]cyclohexanamide, dihydrochloride. N-[2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(2- methoxyphenyl)carbonyl]-1 H-1 ,4-benzodiazepin-8-yl]cyclohexanamide, dihydrochloride.
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonic acid, ethyl ester, hydrochloride.
(3R)-7-Bromo-1-[cyano(1 H-imidazol-4-yl)methyl]-2,3,4,5-tetrahydro-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(3R)-1 -[2-Amino-1 -(1 H-imidazol-4-yl)ethyl]-2,3,4,5-tetrahydro-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(3R)-1 -[2-(Dimethylamino)-1 -(1 H-imidazol-4-yl)ethyl]-2,3,4,5-tetrahydro-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(3R)-1 -[2-Amino-1 -(1 H-imidazol-4-yl)ethyl]-7-bromo-2,3,4,5-tetrahydro-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (3R)-1-[2-(Dimethylamino)-1-(1 H-imidazol-4-yl)ethyl]-7-bromo-2,3,4,5- tetrahydro-4-(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
7-Cyano-1 ,3,4,5-tetrahydro-1 -(1 -methyl-1 H-imidazol-5-ylmethyl)-3-
(phenylmethyl)-4-(phenylsulfonyl)-2H-1 ,4-benzodiazepin-2-one, monohydrochloride.
7-Cyano-1 ,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-
(phenylsulfonyl)-2H-1 ,4-benzodiazepin-2-one, monohydrochloride.
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(2-phenylethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 7-Bromo-3-[(3-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Bromo-3-(cyclohexylmethyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 7-Bromo-3-[(2-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (S)-7-Bromo-3-(cyclohexylmethyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[(4- methoxyphenyl)methyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 4-Acetyl-7-bromo-3-[(2-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 4-Acetyl-7-bromo-3-[(3-chlorophenyl)methyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-[(4- hydroxyphenyl)methyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-7- phenyl-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 2,3,4,5-Tetrahydro-8-(hydroxymethyl)-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(1-naphthalenylcarbonyl)- 8-(phenoxymethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. N-Cyclohexyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8-carboxamide, dihydrochloride.
N-(Cyclohexylmethyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1 - naphthalenylcarbonyl)-1 H-1 ,4-benzodiazepine-8-carboxamide, dihydrochloride.
2,3,4, 5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(1-naphthalenylcarbonyl)- N-(phenylmethyl)-1 H-1 ,4-benzodiazepine-8-carboxamide, dihydrochloride. (R)-4-Acetyl-7-[2-[(dimethylamino)methyl]phenyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(1-oxobutyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-methyl-1 - oxopropyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(2-pyridinylacetyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 - methylethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyI)-3-
(phenylmethyl)-4-[(trifluoromethyl)sulfonyl]-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-3-
(phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-3- (phenylmethyl)-
4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1-(1H-imidazol-
4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-4-[(3-cyanophenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol- 4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 -methyl-1 H- imidazol-2-yl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-4-[(3-Bromophenyl)sulfonyl]-7-cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol- 4-ylmethyl)-3-(phenylmethyl)-1H-1 ,4-benzodiazepine, monohydrochloride.
(R)-N-[5-[[7-cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)- 1 H-1 ,4-benzodiazepin-4-yl]sulfonyl]-4-methyl-2-thiazolyl]acetamide, dihydrochloride.
4-Acetyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-7-
(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(2-phenyl-1 ,2-dioxoethyl)-
7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-
(trifluoromethoxy)benzoyl]-1 H-1 ,4-benzodiazepine, trihydrochloride. (R)-2,3,4,5-Tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4- (methylsulfonyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-4-(phenylacetyl)-
3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
4-(2-Benzothiazolyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-
1 H-1 ,4-benzazepine, trihydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-7-(3- pyridinyl)-4-(trifluoroacetyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-7-(3-pyridinyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
7-Bromo-3-[(1 , 1 -dimethylethoxy)methyl]-1 ,2,3,4-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-5H-1 ,4-benzodiazepin-5-one.
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenoxymethyl)-l H-1 ,4-benzodiazepine, dihydrochloride.
7-Bromo-2,3,4,5-tetrahydro-3-(hydroxymethyl)-1-(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-l H-1 ,4-benzodiazepine, monohydrochloride. 7-Bromo-3-[(1 ,1-dimethylethoxy)methyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine. [7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2-methylpropyl ester, trihydrochloride. [4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2-methylpropyl ester.
N-[4-Acetyl-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepin-8-yl]cyclohexanecarboxamide, dihydrochloride. [7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-
3-(phenylmethyl)-1 H-1 ,4-benzodiazepin-8-yl]carbamic acid, 2-methylpropyl ester. (R)-2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(phenylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile, monohydrochloride.
7-Bromo-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
4H-1 ,4-benzodiazepine-4-acetamide. 7-Bromo-4-[(dimethylamino)acetyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine.
(R)-7-Bromo-4-(1 ,2-dioxopropyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
(R)-7-Bromo-4-(cyclopropylcarboonyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1H-1 ,4-benzodiazepine, trifluoroacetate.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
7-Bromo-2,3,4,5-tetrahydro-1 ,4-bis(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
7-Bromo-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N-dimethyl-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonamide, monohydrochloride.
2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile, monohydrochloride. (R)-7-Cyano-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-yimethyl)-N,N-dimethyl-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxamide, monohydrochloride.
N,N-Diethyl-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7-carboxamide, monohydrochloride. 2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-4-(1-phenyl-1H- tetrazol-5-yl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(2-pyrazinylcarbonyl)-4H-1 ,4-benzodiazepine, monohydrochloride. (R)-4-[7-Bromo-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4H-1 ,4-benzodiazepin-4-yl]-4-oxobutanoic acid, methyl ester, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(4- morpholinylcarbonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[[2-(1-pyrrolidinyl)ethyl]sulfonyl]-1 H-1 ,4-benzodiazepine, dihydrochloride.
(S)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-7- phenyl-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-3-(3- pyridinyimethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7-phenyl-4- (propylsulfonyl)-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(2-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-7-(2-pyrimidinyl)-1 H-1 ,4-benzodiazepine,dihydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[(trifluoromethyl)sulfonyl]-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-7-phenyl-3-
(phenylmethyl)-4-(trifluoroacetyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-3-
(phenylmethyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-7-(4- pyridinyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-
(phenylsulfonyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4- (propylsulfonyl)-7-(4-pyridinyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[(3,5-dimethyl-isoxazol-4-yl)sulfonyl]-1 H-1 ,4- benzodiazepine, dihydrochloride.
(R)-7-Cyano-4-[(4-cyanophenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol- 4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[(2,2,2-trifluoroethyl)sulfonyl]-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-[(5-Bromo-2-thienyl)sulfonyl]-7-cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol- 4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(4- methoxyphenyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
N-[[7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (methylsulfonyl)-l H-1 ,4-benzodiazepin-3-yl]methyl]benzamide, dihydrochloride.
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N-dimethyl-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonamide, hydrochloride.
(R)-7-Cyano-1 ,2,3,5-tetrahydro-N,N-dimethyl-1-[(1 -methyl-1 H-imidazol-5- yl)methyl]-3-(phenylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonamide, hydrochloride.
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Chloro-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Chloro-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4- (phenylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(pyridin-3- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, tetrahydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-2-ylmethyl)-4- (methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(1 -methyl-1 H- imidazol-4-yl)sulfonyl3-3-(phenylmethyl)-1H-1 ,4-benzodiazepine, trihydrochloride.
(R)-7-Chloro-2,3,4,5-tetrahydro-1-(1-methyl-imidazol-5-ylmethyl)-4-[(2- morpholin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Chloro-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(2-morpholin-
4-yl-ethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Chloro-4-[(dimethylamino)sulfonyl]-1 -[(1 -methyl-1 H-imidazol-5- yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Chloro-2,3,4,5-tetrahydro-1-(1 -methyl-imidazol-5-ylmethyl)-4-[(4- methyl-piperidin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1-methyl-imidazol-5-ylmethyl)-4-[(4- methyl-piperidin-4-yl-ethyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4- benzodiazepine, dihydrochloride.
(R)-7-Cyano-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4H-1 ,4-benzodiazepine-4-carboxylic acid, isopropyl ester, hydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-4-[[2-(1 H-imidazol-1-yl)ethyl]sulfonyl]-1-(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(propylsulfonyl)-3-(3-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
1 H-1 ,4-benzodiazepin-5-one, hydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-1 -ylacetyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate. 1 ,2,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-2-(2-phenylethyl)-3H-1 ,4- benzodiazepin-3-one.
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-2-(2- phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-7- phenyl-3-(4-pyridinylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1 H-imidazol-2-ylmethyl)-4-(phenylsulfonyl)-3-
(phenylmethyl)-l H-1 ,4-benzodiazepine-7-carbonitrile, hydrochloride. (R)-7-Cyano-1 ,2,3,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-N,N-dimethyl-3-
(3-pyridinylmethyl)-4H-1 ,4-benzodiazepine-4-carboxamide, dihydrochloride. (R)-7-Cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-N,N-dimethyl-3-
(3-pyridinylmethyl)-4H-1 ,4-benzodiazepine-4-sulfonamide, dihydrochloride. 4-[(4-Fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5- yl)-3-(phenylmethyl)-1 H-thieno[2,3-e]-1 ,4-diazepine, monohydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1-(4-cyanophenylmethyl)-imidazol-5-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7-carbonitrile, hydrochloride.
(R)-2,3,4,5-Tetrahydro-1-(1-(4-cyanophenylmethyl)-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7-carbonitrile, hydrochloride.
(R)-4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-3-
(pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-3- (pyridin-3-ylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4-yl)methyl]-3-(pyridin-3- ylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-7-phenyl- 3-(phenylmethyl)-1H-1 ,4-benzodiazepine.
1 ,2,3,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-N-(1-naphthalenyl)-7-phenyl-
4H-1 ,4-benzodiazepine-4-carboxamide, monohydrochloride.
(S)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. N-[2,3,4,5-Tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(2,3-dimethylbenzoyl)-
1 H-1 ,4-benzodiazepin-8-yl]cyclohexanecarboxamide, dihydrochloride.
(R)-7-Cyano-N-[2-(dimethylamino)ethyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-N-methyl-3-(phenyimethyl)-1 H-1 ,4-benzodiazepine-4- carboxamide, trifluoroacetate (1 :2). 7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(methylsulfonyl)-2- oxo-3-(phenylmethyl)-1H-1 ,4-benzodiazepine, trifluoroacetate.
(R)-7-Cyano-4-(2-furanylcarbonyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :1).
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[(4- nitrophenyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluroracetate. (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[[4-(4-methyl-1 piperazinyl)phenyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-[[(4- dimethylamino)phenyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate.
(R)-7-Bromo-4-[[2-(dimethylamino)ethyl]sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-(3-pyridinylsulfonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)- 4-(methylsulfonyl)-3-
(phenylmethyl)-1 H-1 ,4-benzo-diazepine, dihydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-4-yl)methyl]-4-
(methylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-4-[[3-(Dimethylamino)propyl]sulfonyl]-2,3,4,5-tetrahydro-1-(1 H-imidazol-
4-ylmethyl)-7-phenyl-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-1 H-1 ,4-benzodiazepine, trihydrochloride.
4-Butyl-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-
1 ,4-benzodiazepine, trihydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[[2-(4- morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4-[[2- (4-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-1H-1 ,4-benzodiazepine, dihydrochloride. (R)-7-Cyano-1-(1H-imidazol-4-ylmethyl)-4-(4-morpholinylsulfonyl)-3- (phenylmethyl)-l H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Cyano-1 -[(1 -methyl-1 H-imidazol-5-yl)methyl]-4-[(4- morpholinyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(4- aminophenyl)sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. 2,3,4,5-Tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-[(4-pyridylthio)acetyl]-7- phenyl-1 H-1 ,4-benzodiazepine, dihydrochloride.
N-(4-Chlorophenyl)-N'-cyano-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-7-phenyl-4H-1 ,4-benzodiazepine-4-imidamide, monohydrochloride.
4-Acetyl-7-bromo-1 ,2,4,5,1 ',3'-hexahydro-1 -(1 H-imidazol-4- ylmethyl)spiro[3H-1 ,4-benzodiazepine-3,2'-[2H]indene], dihydrochloride.
7-Bromo-4-[3-(dimethylamino)-1 -oxopropyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, trifluoroacetate (1 :1).
(R)-2,3,4,5-Tetrahydro-1 -(1 -methyl-1 H-imidazol-5-ylmethyl)-4-
(phenylsulfonyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine-7-carbonitrile, monohydrochloride.
2,3,4,5-Tetrahydro-1 -[(1 -methyl-1 H-imidazol-5-yl)-methyl)-4-(methyl- sulfonyl)-7-phenyl-3-(pyridin-3-yl-methyl)-1 H-1 ,4-benzodiazepine, hydrochloride (1 :1.5), trifluoroacetate (1 :0.75) salt.
4-[4-(Fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-
2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-yl-methyl)-4-(methyl-sulfonyl)- 2-(2-phenylethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 -methyl-1 H-imidazol-5-ylmethyl)-4-[[2-
(1-morpholinyl)ethyl]sulfonyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, dihydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-4-(methyl- sulfonyl)-3-(4-bromophenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(methyl- sulfonyl)-3-(thiazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-4-(propyl- sulfonyl)-3-(thiazol-4-ylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-
(propylsulfonyl)-3-(4-bromophenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
(R)-7-Bromo-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(pyridin-3- ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, trihydrochloride. (R)-7-Bromo-2,3,4,5-tetrahydro-1 -(1 H-1 -methyl-imidazol-5-ylmethyl)-3-
(pyridin-3-ylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine, dihydrochloride. 1 ,2,3,4-Tetrahydro-7-bromo-4-[(1 H-imidazol-4-yl)methyl]-2-phenylmethyl-1 -
(phenyl-methyloxycarbonyl)quinoxaline, hydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4-(phenyl- sulfonyl)-3-(4-cyanophenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Cyano-4-[(N-methyl-N-phenylmethyl)aminosulfonyl]-1 -[(1 H-imidazol-
4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride.
(R)-7-Cyano-4-[N-(tetrahydroisoquinolinyl)sulfonyl]-1-[(1 H-imidazol-4- yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-4- (phenylsulfonyl)-3-(2-thienylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. cis-2,3,4,5-Tetrahydro-1 ,5-bis(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-
1 H-1 ,5-benzodiazepine-2-carboxylic acid ethyl ester, trifluoroacetate (1 :2). (R)-7-Cyano-4-[(N-piperidinyl)sulfonyl]-1-[(1 H-imidazol-4-yl)methyl]-3-
(phenylmethyl)-1 H-1 ,4-benzodiazepine, monohydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-1 -methyl-imidazol-5-ylmethyl)-3-
(phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(pyridin-3- ylmethyl)-4-[[2-(dimethylamino)ethyl]sulfonyl]-1 H-1 ,4-benzodiazepine, trihydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-1 -methyl-imidazol-5-ylmethyl)-3-
(phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
N-(Cyano)-N'-methyl-1 ,2,3,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-7- phenyl-4H-1 ,4-benzodiazepine-4-imidamide, hydrochloride. (R)-7-Cyano-4-[(2-nitrophenyl)-sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H-imidazol-
4-ylmethyl)-3-(phenyl-methyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
R)-7-Cyano-4-[(4-methyl-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Cyano-4-(butylsulfonyl)-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
(R)-7-Cyano-4-[(2-trifluoro-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Cyano-4-[(2-trifluoromethoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1 -
(1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride. (R)-7-Cyano-4-[(2-methoxy-carbonylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1 - (1 H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
(R)-7-Cyano-4-[(2-methyl-sulfonylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1-(1 H- imidazol-4-ylmethyl)-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine, hydrochloride.
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(((4-methylsulfonyl)-phenyl)-sulfonyl)-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(((4-trifluoromethyl)-phenyl)-sulfonyl)-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((3-methoxypropyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((3,4-dimethoxyphenyl)-sulfonyl)-1H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-((4- fluorophenyl)methyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N-cyclopropylmethyl-N-propyl)-aminosulfonyl]-1-[(1 H- imidazol-4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-4-[(N,N-(dibutylamino))-sulfonyl]-1 -[(1H-imidazol-4-yl)methyl]-3- (phenylmethyl)-l H-1 ,4-benzodiazepine
(R)-7-Chloro-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1-(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-pyrido[3,4-e]-1 ,4-diazepine 1 ,2,3,4-Tetrahydro-7-bromo-4-[(1 H-imidazol-4-yl)methyl]-2-phenylmethyl-1 - (methylsulfonyl)quinoxaline
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((imidazol-4-yl)methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-((2- thienyl)methyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-((2- thienyl)methyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((3-methylthiopropyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(((3-methylthioxo)-propyl)-sulfonyl)-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(((3-methylsulfonyl)-propyl)-sulfonyl)-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((2-methylpropyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(cyclopentylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((4,4,4-trifluorobutyl)-sulfonyl)-1H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((phenylmethyl)-sulfonyl)-1H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[[2-(5-(N-benzoyl)-aminomethyl)-thienyl]-sulfonyl]-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[[2-(1-(3-chloro-5-methyl-pyridin-2-yl))-pyrrolyl]-sulfonyl]-
1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((4-carboxyphenyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-[((3-methyl-1 ,2,4-oxadiazol-5-yl)-phenyl)-sulfonyl]-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-
(phenylmethyl)-4-((2,5-dimethoxyphenyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N-tetrahydroquinolinyl)sulfonyl]-
1 -[(1 H-imidazol-4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N,N-bis-[1 -(2-methylpropyl)amino]-sulfonyl]-1 -[(1 H-imidazol- 4-yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-4-[(N-methyl-N-phenyl)aminosulfonyl]-1-[(1 H-imidazol-4- yl)methyl]-3-(phenylmethyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(2-(2,6- dimethylphenyl)-ethyl)-4-(methylsulfonyl)-1H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 -(N-phthalimidoethyl)-imidazol-5- ylmethyl)-3-(phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -[(2-(N,N-dimethylamino)-ethyl)-imidazol-5- ylmethyl]-3-(phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-[(2-aminoethyl)-imidazol-5-ylmethyl]-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Bromo-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-thieno[2,3-e]-1 ,4-diazepine (R)-7-Bromo-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1 -[(1 H-imidazol-4- ylmethyl)-3-(phenylmethyl)-1 H-thieno[3,2-e]-1 ,4-diazepine (R)-4-(methanesulfonyl)-2,3,4,5-tetrahydro-1-[(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-l H-8-oxo-pyrimidino[4,5-e]-1 ,4-diazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-((4-(2- methoxyethoxy)-phenyl)methyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-((4-(2- (dimethylamino)-ethoxy)-phenyl)methyl)-4-(phenylsulfonyl)-1H-1 ,4- benzodiazepine ( R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylsulfonyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)-1 -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)-1 -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(R)-1-phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)-1 -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)-1 -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)-1 -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)-1 -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)-1-phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)-1 -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)-1 -phenyl- ethyl]-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)-1 -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)-1 -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)-1 -phenyl- ethyl]-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)-1 -phenyl- ethyl]-4- { propyl sulfonyl) -1H-1, 4 -benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)-1 -phenyl- ethyl]-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)-1 -phenyl- ethyl]-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(R)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(R)-[(S)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(R)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine 7-Cyano-2,3,4,5-tetrahydro-1 -(1H-imidazol-4-ylmethyl)-3-(S)-[(S)- phenylcyclopropyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[(2-(5-(pyridin-2-yl))-thienyl)-sulfonyl])-1 H-1 ,4- benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-[(2-(5-(1 ,2-isoxazol-3-yl))-thienyl)-sulfonyl])-1 H-1 ,4- benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-(phenylsulfonyl)-1H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1 -(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(3-(1 H-imidazol-2-yl)-propyl)-3- (phenylmethyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(2-(1 H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-(phenylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(2-(1 H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-(methylsulfonyl)-1 H-1 ,4-benzodiazepine
(R)-7-Cyano-2,3,4,5-tetrahydro-1-(2-(1H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-(propylsulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1-(2-(1 H-imidazol-2-yl)-ethylsulfonyl)-3- (phenylmethyl)-4-((2-thienyl)-sulfonyl)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-((1 -oxoethyl)-amino)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(methanesulfonylamino)-1 H-1 ,4-benzodiazepine (R)-7-Cyano-2,3,4,5-tetrahydro-1 -(1 H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(phenylsulfonylamino)-1 H-1 ,4-benzodiazepine
5
8. A method of inhibiting farnesyl protein transferase which comprises administering to a mammalian subject an effective farnesyl protein transferase inhibiting amount of a compound of Claim 1.
0 9. A method of inhibiting prenyl transferases which comprises administering to a mammalian subject an effective prenyl transferase inhibiting amount of a compound of Claim 1.
10. A method of inhibiting tumors which comprises administering to 5 a mammalian subject an effective tumor inhibiting amount of a compound of
Claim 1.
11. A method of treating diseases associated with signal transduction pathways operating through Ras which comprises 0 administering to a mammalian subject an amount of a compound of Claim 1 effective for treating said diseases.
12. A method of treating diseases associated with proteins that are post-translationally modified by the enzyme famesyl protein transferase 5 which comprises administering to a mammalian subject an amount of a compound of Claim 1 effective for treating said diseases.
13. A method of treating disease associated with proteins that are post-translationally modified by the enzymes geranylgeranyl protein o transferase which comprises administering to a mammalian subject an amount of a compound of Claim 1 effective for treating said diseases.
14. A compound of the formula
Figure imgf000422_0001
wherein Ri is selected from Cl, Br, phenyl, pyridyl or cyano and R2 is selected from substituted aralkyl or substituted heterocycloalkyi.
15. A compound of the formula
Figure imgf000422_0002
wherein R is selected from Cl, Br, phenyl, pyridyl or cyano and R2 is selected from substituted aralkyl or substituted heterocycloalkyi.
16. A compound of the formula
Figure imgf000422_0003
wherein Ri is selected from Cl, Br, phenyl, pyridyl or cyano; R2 is selected from substituted aralkyl or substituted heterocycloalkyi; R3 is selected from substituted alkyl, substituted aryl or substituted heterocyclo; Zi is selected from CO, SO2, CO2, CONHR5, SO3, SO2NR5, C(NCN)NRs; R5 is selected from hydrogen, lower alkyl, substituted alkyl, aryl or substituted aryl.
17. A compound of the formula
Figure imgf000423_0001
wherein Ri is selected from Cl, Br, phenyl, pyridyl or cyano; R2 is selected from substituted aralkyl or substituted heterocycloalkyi; R3 is selected from substituted alkyl, substituted aryl or substituted heterocyclo; Zi is selected from CO, SO2, CO2, CONHR5, SO3, SO2NR5, or C(NCN)NRs, Prot is triphenylmethyl or Boc, R5 is selected from hydrogen, lower alkyl, substituted alkyl, aryl or substituted aryl.
PCT/US1997/002920 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase WO1997030992A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
EE9800262A EE04309B1 (en) 1996-02-26 1997-02-24 Farnesyl protein transferase inhibitors
PL328868A PL191502B1 (en) 1996-02-26 1997-02-24 Inhibitors of pharnesil protein transferase
BR9707614A BR9707614A (en) 1996-02-26 1997-02-24 Farnesyl protein transferase inhibitors
JP53039597A JP4115529B2 (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase
UA98084564A UA52642C2 (en) 1996-02-26 1997-02-24 Farnesyl-protein transferase inhibitors
AU21366/97A AU718676B2 (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase
NZ330287A NZ330287A (en) 1996-02-26 1997-02-24 Substituted 1,4-benzodiazepine inhibitors of farnesyl protein transferase
CA002239187A CA2239187C (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase
IL12419797A IL124197A (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase
EP97906761A EP0892797A4 (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase
SK1173-98A SK286568B6 (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase
IL14190897A IL141908A (en) 1996-02-26 1997-02-24 1,4-benzodiazepine derivatives
RO98-01326A RO121118B1 (en) 1996-02-26 1997-02-24 Benzodiazepine derivatives, pharmaceutical compositions comprising the same, and use thereof as inhibitors of farnesyl protein transferase
LVP-98-129A LV12150B (en) 1996-02-26 1998-06-04 Inhibitors of farnesyl protein transferase
NO19983892A NO319395B1 (en) 1996-02-26 1998-08-25 Inhibitors for farnesyl protein transferase and its use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1226596P 1996-02-26 1996-02-26
US60/012,265 1996-02-26
US2280596P 1996-07-25 1996-07-25
US60/022,805 1996-07-25

Publications (1)

Publication Number Publication Date
WO1997030992A1 true WO1997030992A1 (en) 1997-08-28

Family

ID=26683350

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/002920 WO1997030992A1 (en) 1996-02-26 1997-02-24 Inhibitors of farnesyl protein transferase

Country Status (24)

Country Link
US (2) US6011029A (en)
EP (2) EP1481975A1 (en)
JP (1) JP4115529B2 (en)
KR (1) KR100522983B1 (en)
CN (2) CN100376569C (en)
AU (1) AU718676B2 (en)
BG (1) BG64951B1 (en)
BR (1) BR9707614A (en)
CA (1) CA2239187C (en)
CZ (1) CZ299762B6 (en)
EE (1) EE04309B1 (en)
GE (1) GEP20022616B (en)
HU (1) HUP9902016A3 (en)
IL (2) IL141908A (en)
LV (1) LV12150B (en)
NO (1) NO319395B1 (en)
NZ (1) NZ330287A (en)
PL (1) PL191502B1 (en)
RO (1) RO121118B1 (en)
RU (1) RU2225405C2 (en)
SK (1) SK286568B6 (en)
TW (1) TW496863B (en)
UA (1) UA52642C2 (en)
WO (1) WO1997030992A1 (en)

Cited By (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018951A1 (en) * 1997-09-29 1999-04-22 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
EP0918771A1 (en) * 1996-07-15 1999-06-02 Bristol-Myers Squibb Company Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase
WO2000003743A2 (en) * 1998-07-15 2000-01-27 Mitotix, Inc. Use of inhibitors of prenyltransferases for inhibiting fungal growth
US6071903A (en) * 1998-01-27 2000-06-06 American Cyanamid Company 2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-hydroxyamic acids
EP1019529A1 (en) * 1997-08-27 2000-07-19 Merck & Co., Inc. A method of treating cancer
US6100395A (en) * 2000-01-10 2000-08-08 Bristol-Myers Squibb Company Reductive alkylation of secondary amines with hydrosilane
EP1049664A1 (en) * 1997-12-22 2000-11-08 Bayer Corporation Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
FR2796943A1 (en) * 1999-07-30 2001-02-02 Aventis Pharma Sa BENZOXAZINN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USE IN THERAPEUTICS
EP1088821A1 (en) * 1999-09-28 2001-04-04 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives
US6271197B1 (en) 1996-04-11 2001-08-07 Gpc-Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6284755B1 (en) 1998-12-08 2001-09-04 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
WO2001081322A1 (en) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
US6316436B1 (en) 1998-12-08 2001-11-13 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1158982A2 (en) * 1999-03-03 2001-12-05 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US6455281B1 (en) 1996-04-11 2002-09-24 Gpc Biotech Inc. Nucleic acids for identifying anti-fungal agents, and uses related thereto
US6462086B1 (en) * 1999-06-18 2002-10-08 Ramot University Authority For Applied Research And Industrial Development Ltd. Non-malignant disease treatment with Ras antagonists
JP2002535253A (en) * 1999-01-21 2002-10-22 ブリストル−マイヤーズ スクイブ カンパニー Complex of ras farnesyltransferase inhibitor and sulfobutylether-7-β-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin, and method for producing the same
EP1283055A1 (en) * 2000-04-07 2003-02-12 Takeda Chemical Industries, Ltd. Soluble beta amyloid precursor protein secretion promoters
US6645966B2 (en) 2001-01-22 2003-11-11 Schering Corporation Treatment of malaria with farnesyl protein transferase inhibitors
WO2003104178A1 (en) * 2002-06-07 2003-12-18 Cortical Pty Ltd Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
US6696280B2 (en) 1996-04-11 2004-02-24 Gpc Biotech, Inc. Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto
WO2004085388A2 (en) 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6838467B2 (en) 2000-02-24 2005-01-04 Janssen Pharmaceutica N. V. Dosing regimen
WO2005084295A2 (en) 2004-03-01 2005-09-15 Bristol-Myers Squibb Company Fused heterotricyclic compounds as inhibitors of 17b-hydroxysteroid dehydrogenase 3
US6946485B2 (en) 1999-06-18 2005-09-20 Ramot At Tel Aviv University, Ltd. Treatment of post-angioplasty restenosis and atherosclerosis with Ras antagonists
WO2005087232A1 (en) 2004-03-04 2005-09-22 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
EP1591120A1 (en) * 2003-01-28 2005-11-02 Takeda Chemical Industries, Ltd. Receptor agonists
US7034055B1 (en) 1999-06-30 2006-04-25 Prescient Neuropharma Inc. 2-aminoindane analogs
WO2006104008A1 (en) * 2005-03-25 2006-10-05 Kissei Pharmaceutical Co., Ltd. Urea derivative, medicinal composition containing the same, and medicinal use of these
EP1742640A2 (en) * 2004-04-27 2007-01-17 The Regents of The University of Michigan Technology Management Wolverine Tower Office Methods and compositions for treating diseases and conditions associated with mitochondrial function
WO2007024949A3 (en) * 2005-08-25 2007-06-07 Schering Corp Alpha2c adrenoreceptor agonists
WO2006052718A3 (en) * 2004-11-05 2007-06-28 Janssen Pharmaceutica Nv Farnesyltransferase inhibitors for treating sepsis
EP1938821A2 (en) 2001-01-25 2008-07-02 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
US7405234B2 (en) 2002-05-17 2008-07-29 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
EP1958625A1 (en) 2004-11-18 2008-08-20 Brystol-Myers Squibb Company Enteric coate bead comprising ixabepilone and preparation thereof
WO2008100463A1 (en) 2007-02-13 2008-08-21 Schering Corporation 3,4-dihydr0-l,4-benz0xazine, 3, 4-dihydr0-1, 4-benzothiazine and 1,2,3,4-tetrahydro-quinoxaline derivatives as alpha2c adrenoreceptor agonists
US7417026B2 (en) 2003-08-13 2008-08-26 Children's Hospital Medical Center Mobilization of hematopoietic cells
WO2008153858A1 (en) 2007-06-05 2008-12-18 Schering Corporation Polycyclic indazole derivatives and their use as erk inhibitors for the treatment of cancer
US7632858B2 (en) 2002-11-15 2009-12-15 Bristol-Myers Squibb Company Open chain prolyl urea-related modulators of androgen receptor function
EP2163538A1 (en) * 2007-05-25 2010-03-17 Topharman Shanghai Co., Ltd. Preparation methods of 4-acetyl-2,3,4,5-tetrahydro- benzo[1,4]diazepine and their intermediates
US7683046B2 (en) 1999-04-30 2010-03-23 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US7687499B2 (en) 2005-09-16 2010-03-30 Janssen Pharmaceutica Nv Cyclopropyl amines as modulators of the histamine H3 receptor
US7696241B2 (en) 2004-03-04 2010-04-13 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
US7759323B2 (en) 2001-05-22 2010-07-20 Eisai R & D Management Co., Ltd. Highly purified antiendotoxin compound
US7820702B2 (en) 2004-02-04 2010-10-26 Bristol-Myers Squibb Company Sulfonylpyrrolidine modulators of androgen receptor function and method
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7893257B2 (en) 2006-12-14 2011-02-22 Janssen Pharmaceutica Nv Process for the preparation of piperazinyl and diazepanyl benzamide derivatives
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US7915384B2 (en) 2003-08-13 2011-03-29 Children's Hospital Medical Center Chimeric peptides for the regulation of GTPases
WO2011041152A1 (en) 2009-09-30 2011-04-07 Schering Corporation Novel compounds that are erk inhibitors
EP2308833A2 (en) 1999-04-15 2011-04-13 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US8017749B2 (en) 2006-12-04 2011-09-13 The Board Of Trustees Of The University Of Illinois Compositions and methods to treat cancer with cupredoxins and CpG rich DNA
WO2011163330A1 (en) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Novel heterocyclic compounds as erk inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
WO2012030685A2 (en) 2010-09-01 2012-03-08 Schering Corporation Indazole derivatives useful as erk inhibitors
WO2012087772A1 (en) 2010-12-21 2012-06-28 Schering Corporation Indazole derivatives useful as erk inhibitors
WO2012100206A2 (en) 2011-01-20 2012-07-26 Board Of Regents, The University Of Texas System Mri markers, delivery and extraction systems, and methods of manufacture and use thereof
US8232244B2 (en) 2007-02-08 2012-07-31 The Board Of Trustees Of The University Of Illinois Compositions and methods to prevent cancer with cupredoxins
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
WO2013007172A1 (en) 2011-07-09 2013-01-17 北京市丰硕维康技术开发有限责任公司 Platinum compounds for treating cell proliferative disease, preparation methods and uses thereof
WO2013041014A1 (en) 2011-09-19 2013-03-28 北京市丰硕维康技术开发有限责任公司 Platinum compound having amino- or alkylamino-containing succinic acid derivatives as leaving group, preparation method therefor, and use thereof
WO2013064231A1 (en) 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3)
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
WO2014075391A1 (en) 2012-11-17 2014-05-22 北京市丰硕维康技术开发有限责任公司 Platinum compound of malonic acid derivative having leaving group containing amino or alkylamino
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
US9181188B2 (en) 2002-02-11 2015-11-10 Bayer Healthcare Llc Aryl ureas as kinase inhibitors
WO2015200920A1 (en) 2014-06-27 2015-12-30 The Regents Of The University Of California Cultured mammalian limbal stem cells, methods for generating the same, and uses thereof
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
WO2017031101A1 (en) 2015-08-17 2017-02-23 Kura Oncology, Inc. Methods of treating cancer patients with farnesyl transferase inhibitors
WO2017184968A1 (en) 2016-04-22 2017-10-26 Kura Oncology, Inc. Methods of selecting cancer patients for treatment with farnesyltransferase inhibitors
US9951153B2 (en) 2012-07-31 2018-04-24 Dow Global Technologies Llc Method of making an olefin polymerization catalyst activator
US9956215B1 (en) 2017-02-21 2018-05-01 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2018085518A2 (en) 2016-11-03 2018-05-11 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
WO2018156609A1 (en) 2017-02-21 2018-08-30 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
EP3401314A1 (en) * 2013-03-15 2018-11-14 Araxes Pharma LLC Covalent inhibitors of kras g12c
US10273207B2 (en) 2013-03-15 2019-04-30 Araxes Pharma Llc Covalent inhibitors of kras G12C
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
WO2019113269A1 (en) 2017-12-08 2019-06-13 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US10351550B2 (en) 2015-07-22 2019-07-16 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10370386B2 (en) 2013-10-10 2019-08-06 Araxes Pharma Llc Substituted quinolines as inhibitors of KRAS G12C
US10377743B2 (en) 2016-10-07 2019-08-13 Araxes Pharma Llc Inhibitors of RAS and methods of use thereof
US10428064B2 (en) 2015-04-15 2019-10-01 Araxes Pharma Llc Fused-tricyclic inhibitors of KRAS and methods of use thereof
WO2020084580A1 (en) 2018-10-26 2020-04-30 Novartis Ag Methods and compositions for ocular cell therapy
WO2020092720A2 (en) 2018-11-01 2020-05-07 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
US10647703B2 (en) 2015-09-28 2020-05-12 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10675326B2 (en) 2004-10-07 2020-06-09 The Board Of Trustees Of The University Of Illinois Compositions comprising cupredoxins for treating cancer
US10689356B2 (en) 2015-09-28 2020-06-23 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
WO2020132437A1 (en) 2018-12-21 2020-06-25 Kura Oncology, Inc. Therapies for squamous cell carcinomas
US10730867B2 (en) 2015-09-28 2020-08-04 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10736897B2 (en) 2017-05-25 2020-08-11 Araxes Pharma Llc Compounds and methods of use thereof for treatment of cancer
US10745385B2 (en) 2017-05-25 2020-08-18 Araxes Pharma Llc Covalent inhibitors of KRAS
WO2020180663A1 (en) 2019-03-01 2020-09-10 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020190604A1 (en) 2019-03-15 2020-09-24 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
WO2020205486A1 (en) 2019-03-29 2020-10-08 Kura Oncology, Inc. Methods of treating squamous cell carcinomas with farnesyltransferase inhibitors
WO2020205387A1 (en) 2019-04-01 2020-10-08 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10806730B2 (en) 2017-08-07 2020-10-20 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020223583A1 (en) 2019-05-02 2020-11-05 Kura Oncology, Inc. Methods of treating acute myeloid leukemia with farnesyltransferase inhibitors
US10829458B2 (en) 2015-04-10 2020-11-10 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
WO2020236940A1 (en) * 2019-05-20 2020-11-26 California Institute Of Technology Kras g12c inhibitors and uses thereof
US10858343B2 (en) 2015-09-28 2020-12-08 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10875842B2 (en) 2015-09-28 2020-12-29 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10882847B2 (en) 2015-09-28 2021-01-05 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US11021470B2 (en) 2015-11-16 2021-06-01 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
US11136308B2 (en) 2017-01-26 2021-10-05 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
WO2021220132A1 (en) 2020-04-27 2021-11-04 Novartis Ag Methods and compositions for ocular cell therapy
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
US11291663B2 (en) 2017-08-07 2022-04-05 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11639346B2 (en) 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS
WO2023143389A1 (en) * 2022-01-29 2023-08-03 江苏恒瑞医药股份有限公司 Fused heterocyclic compound, preparation method therefor, and medical application thereof

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI310684B (en) * 2000-03-27 2009-06-11 Bristol Myers Squibb Co Synergistic pharmaceutical kits for treating cancer
EP1339709B1 (en) * 2000-11-21 2009-06-24 Janssen Pharmaceutica N.V. Farnesyl transferase inhibiting benzoheterocyclic derivatives
ATE323490T1 (en) * 2000-11-28 2006-05-15 Janssen Pharmaceutica Nv FARNESYL PROTEIN TRANSFERA INHIBITORS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE
ES2263684T3 (en) * 2000-12-27 2006-12-16 Janssen Pharmaceutica N.V. DERIVATIVES OF 4-HETEROCICLIL-QUINOLINA AND -QUINAZOLINA THAT INHIBIT THE FARNESIL TRANSFERASA.
JP4351445B2 (en) * 2000-12-27 2009-10-28 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 4-Substituted-quinoline and quinazoline derivatives that inhibit farnesyltransferase
US6905813B2 (en) * 2001-08-29 2005-06-14 Chugai Photo Chemical Co., Ltd. Processing agent for silver halide color photosensitive material and processing method thereof
US20030134846A1 (en) * 2001-10-09 2003-07-17 Schering Corporation Treatment of trypanosoma brucei with farnesyl protein transferase inhibitors
WO2003041658A2 (en) * 2001-11-13 2003-05-22 Bristol-Myers Squibb Company Process for the preparation of 3,7-disubstituted-2,3,4,5- tetrahydro-1h-1,4-benzodiazepine compounds
WO2003077656A1 (en) * 2002-03-15 2003-09-25 Ciba Specialty Chemicals Holding Inc. 4-aminopyrimidines and their use for the antimicrobial treatment of surfaces
WO2003106628A2 (en) * 2002-06-17 2003-12-24 Bristol-Myers Squibb Company Benzodiazepine inhibitors of mitochondial f1f0 atp hydrolase and methods of inhibiting f1f0 atp hydrolase
AU2003259717A1 (en) * 2002-08-07 2004-02-25 Bristol-Myers Squibb Company Modulators of rabggt and methods of use thereof
JP2004346059A (en) * 2003-01-28 2004-12-09 Takeda Chem Ind Ltd Receptor agonist
US7157446B2 (en) * 2003-05-02 2007-01-02 Bristol Myers Squibb Company Complex of ras-farnesyltransferase inhibitor, a cyclodextrin, and ethanol
US7256208B2 (en) * 2003-11-13 2007-08-14 Bristol-Myers Squibb Company Monocyclic N-Aryl hydantoin modulators of androgen receptor function
US7517890B2 (en) 2003-11-20 2009-04-14 Children's Hospital Medical Center GTPase inhibitors and methods of use
US20050182105A1 (en) * 2004-02-04 2005-08-18 Nirschl Alexandra A. Method of using 3-cyano-4-arylpyridine derivatives as modulators of androgen receptor function
US7388027B2 (en) * 2004-03-04 2008-06-17 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
JP2007538004A (en) * 2004-03-18 2007-12-27 ザ ブライハム アンド ウイメンズ ホスピタル， インコーポレイテッド How to treat synucleinopathy
US20050277629A1 (en) * 2004-03-18 2005-12-15 The Brigham And Women's Hospital, Inc. Methods for the treatment of synucleinopathies (Lansbury)
US20050272722A1 (en) * 2004-03-18 2005-12-08 The Brigham And Women's Hospital, Inc. Methods for the treatment of synucleinopathies
US20070293539A1 (en) * 2004-03-18 2007-12-20 Lansbury Peter T Methods for the treatment of synucleinopathies
US20050272068A1 (en) * 2004-03-18 2005-12-08 The Brigham And Women's Hospital, Inc. UCH-L1 expression and cancer therapy
US20050288298A1 (en) * 2004-03-18 2005-12-29 The Brigham And Women's Hospital, Inc. Methods for the treatment of synucleinopathies
US7323455B2 (en) * 2004-03-24 2008-01-29 Wyeth 7-aryl 1,5-dihydro-4,1-benzoxazepin-2(3H)-one derivatives and their use as progesterone receptor modulators
US20060194821A1 (en) * 2005-02-18 2006-08-31 The Brigham And Women's Hospital, Inc. Compounds inhibiting the aggregation of superoxide dismutase-1
US20060235006A1 (en) * 2005-04-13 2006-10-19 Lee Francis Y Combinations, methods and compositions for treating cancer
EP2527337A1 (en) * 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
AU2006257919A1 (en) * 2005-06-09 2006-12-21 Bristol-Myers Squibb Company Methods of identifying and treating individuals exhibiting mutant kit protein
EP1920048A4 (en) 2005-07-29 2009-12-09 Childrens Hosp Medical Center Gtpase inhibitors and methods of use and crystal structure of rac-1 gtpase
US20090099197A1 (en) * 2005-11-15 2009-04-16 Bristol-Myers Squibb Company Methods of Identifying and Treating Individuals Exhibiting MDR-1 Overexpression With Protein Tyrosine Kinase Inhibitors and Combinations Thereof
JP5243970B2 (en) * 2006-02-14 2013-07-24 バーテックス ファーマシューティカルズ インコーポレイテッド Dihydrodiazepines useful as inhibitors of protein kinases
WO2008089135A2 (en) * 2007-01-12 2008-07-24 University Of South Florida Identification of biomarkers predictive of dasatinib effects in cancer cells
AU2008251557B2 (en) * 2007-05-10 2012-12-06 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2009105140A2 (en) 2007-12-11 2009-08-27 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
US8232402B2 (en) * 2008-03-12 2012-07-31 Link Medicine Corporation Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications
LT2303270T (en) * 2008-05-05 2017-09-11 Sanofi Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals
WO2010014784A2 (en) 2008-08-01 2010-02-04 Bristol-Myers Squibb Company Combination of anti-ctla4 antibody with diverse therapeutic regimens for the synergistic treatment of proliferative diseases
US20110060005A1 (en) * 2008-11-13 2011-03-10 Link Medicine Corporation Treatment of mitochondrial disorders using a farnesyl transferase inhibitor
MX2011005096A (en) * 2008-11-13 2011-11-18 Link Medicine Corp Azaquinolinone derivatives and uses thereof.
US20100331363A1 (en) * 2008-11-13 2010-12-30 Link Medicine Corporation Treatment of mitochondrial disorders using a farnesyl transferase inhibitor
WO2010138487A1 (en) * 2009-05-26 2010-12-02 Exelixis, Inc. BENZOXAZEPINES AS INHIBITORS OF PI3K/m TOR AND METHODS OF THEIR USE AND MANUFACTURE
ES2629167T3 (en) 2009-07-20 2017-08-07 Bristol-Myers Squibb Company Combination of anti-CTLA4 antibody with etoposide for the synergistic treatment of proliferative diseases
AU2014201036B2 (en) * 2010-04-06 2015-07-16 Nippon Soda Co., Ltd Nitrogen-containing heterocyclic compound and method for producing same
BR122017022928B1 (en) * 2010-04-06 2018-03-06 Nippon Soda Co., Ltd. METHOD FOR PRODUCTION OF NITROGEN CONTAINING HYPEROCYCLIC COMPOUND
WO2013166043A1 (en) 2012-05-02 2013-11-07 Children's Hospital Medical Center Rejuvenation of precursor cells
US10028503B2 (en) 2014-06-18 2018-07-24 Children's Hospital Medical Center Platelet storage methods and compositions for same
CN115028617A (en) * 2016-05-24 2022-09-09 基因泰克公司 Heterocyclic inhibitors of CBP/EP300 and their use in the treatment of cancer
WO2019055877A1 (en) 2017-09-15 2019-03-21 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as cbp/p300 inhibitors
SG11202012767UA (en) 2018-06-29 2021-01-28 Forma Therapeutics Inc Inhibiting creb binding protein (cbp)
US11801243B2 (en) 2020-09-23 2023-10-31 Forma Therapeutics, Inc. Bromodomain inhibitors for androgen receptor-driven cancers
US11795168B2 (en) 2020-09-23 2023-10-24 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP)
CN115745960A (en) * 2021-09-02 2023-03-07 中国科学院上海药物研究所 Quinolinone amide-containing compound, preparation method, pharmaceutical composition and application thereof
CN114230529A (en) * 2021-11-03 2022-03-25 河南大学 Tetrahydroquinoxaline sulfonamide derivative and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5441952A (en) * 1993-04-05 1995-08-15 Merck & Co., Inc. Fibrinogen receptor antagonists

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1923821A1 (en) * 1969-05-09 1970-11-19 Wuelfing J A Fa Tetrahydrobenzodiazepinedione derivs with - valuable cns properties
JPS6168487A (en) * 1984-09-12 1986-04-08 Sumitomo Chem Co Ltd Carbamoylazole derivative, its production, and herbicide comprising it as active ingredient
EP0322779A3 (en) * 1987-12-29 1991-05-08 Yoshitomi Pharmaceutical Industries, Ltd. Benzolactam compounds and pharmaceutical uses thereof
JP2729545B2 (en) 1991-06-05 1998-03-18 富士写真フイルム株式会社 Processing solution for silver halide color photographic light-sensitive material and processing method using the same
US5352705A (en) * 1992-06-26 1994-10-04 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
CA2152631A1 (en) * 1992-12-21 1994-07-07 William Edward Bondinell Bicyclic fibrinogen antagonists
AU6219994A (en) * 1993-03-11 1994-09-26 Yamanouchi Pharmaceutical Co., Ltd. Compound with vasopressin antagonism
CA2118985A1 (en) * 1993-04-02 1994-10-03 Dinesh V. Patel Heterocyclic inhibitors of farnesyl protein transferase
US5843941A (en) 1993-05-14 1998-12-01 Genentech, Inc. Ras farnesyl transferase inhibitors
JP3597863B2 (en) * 1993-11-05 2004-12-08 ワーナー−ランバート・コンパニー Protein: substituted di- and tripeptide inhibitors of farnesyltransferase
US5753650A (en) * 1994-05-20 1998-05-19 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
EP0767792A4 (en) * 1994-06-29 2002-11-20 Smithkline Beecham Corp Vitronectin receptor antagonists
US5977101A (en) * 1995-06-29 1999-11-02 Smithkline Beecham Corporation Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity
EP1007525A1 (en) 1997-08-29 2000-06-14 Zeneca Limited Aminometyl oxooxazolidinyl benzene derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5441952A (en) * 1993-04-05 1995-08-15 Merck & Co., Inc. Fibrinogen receptor antagonists

Cited By (206)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6277564B1 (en) 1996-04-11 2001-08-21 Gpc Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6727082B1 (en) 1996-04-11 2004-04-27 Gpc Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6455281B1 (en) 1996-04-11 2002-09-24 Gpc Biotech Inc. Nucleic acids for identifying anti-fungal agents, and uses related thereto
US6696280B2 (en) 1996-04-11 2004-02-24 Gpc Biotech, Inc. Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto
US6271197B1 (en) 1996-04-11 2001-08-07 Gpc-Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6624157B2 (en) 1996-07-15 2003-09-23 Bristol-Myers Squibb Company Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase
EP0918771A4 (en) * 1996-07-15 2001-02-07 Bristol Myers Squibb Co Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase
EP0918771A1 (en) * 1996-07-15 1999-06-02 Bristol-Myers Squibb Company Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase
EP1019529A1 (en) * 1997-08-27 2000-07-19 Merck & Co., Inc. A method of treating cancer
EP1019529A4 (en) * 1997-08-27 2002-09-11 Merck & Co Inc A method of treating cancer
US6458783B1 (en) 1997-09-29 2002-10-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
WO1999018951A1 (en) * 1997-09-29 1999-04-22 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
EP1049664A4 (en) * 1997-12-22 2001-05-16 Bayer Ag Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
EP1449834A2 (en) * 1997-12-22 2004-08-25 Bayer Corporation Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
EP1449834A3 (en) * 1997-12-22 2004-12-22 Bayer Corporation Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
EP1049664A1 (en) * 1997-12-22 2000-11-08 Bayer Corporation Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
US6071903A (en) * 1998-01-27 2000-06-06 American Cyanamid Company 2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-hydroxyamic acids
WO2000003743A3 (en) * 1998-07-15 2001-02-01 Mitotix Inc Use of inhibitors of prenyltransferases for inhibiting fungal growth
US6423519B1 (en) 1998-07-15 2002-07-23 Gpc Biotech Inc. Compositions and methods for inhibiting fungal growth
WO2000003743A2 (en) * 1998-07-15 2000-01-27 Mitotix, Inc. Use of inhibitors of prenyltransferases for inhibiting fungal growth
US6284755B1 (en) 1998-12-08 2001-09-04 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US6316436B1 (en) 1998-12-08 2001-11-13 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
JP2002535253A (en) * 1999-01-21 2002-10-22 ブリストル−マイヤーズ スクイブ カンパニー Complex of ras farnesyltransferase inhibitor and sulfobutylether-7-β-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin, and method for producing the same
AU772204B2 (en) * 1999-01-21 2004-04-22 Bristol-Myers Squibb Company Complex of ras-farnesyltransferase inhibitor and sulfobutylether-7-beta-cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin and method
EP1158982A2 (en) * 1999-03-03 2001-12-05 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1158982A4 (en) * 1999-03-03 2002-06-12 Merck & Co Inc Inhibitors of prenyl-protein transferase
EP2308833A2 (en) 1999-04-15 2011-04-13 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
EP3222619A1 (en) 1999-04-15 2017-09-27 Bristol-Myers Squibb Holdings Ireland Cyclic protein tyrosine kinase inhibitors
US7683046B2 (en) 1999-04-30 2010-03-23 The Regents Of The University Of Michigan Benzodiazepine compositions for treating epidermal hyperplasia and related disorders
US6946485B2 (en) 1999-06-18 2005-09-20 Ramot At Tel Aviv University, Ltd. Treatment of post-angioplasty restenosis and atherosclerosis with Ras antagonists
US6462086B1 (en) * 1999-06-18 2002-10-08 Ramot University Authority For Applied Research And Industrial Development Ltd. Non-malignant disease treatment with Ras antagonists
US7034055B1 (en) 1999-06-30 2006-04-25 Prescient Neuropharma Inc. 2-aminoindane analogs
WO2001009127A1 (en) * 1999-07-30 2001-02-08 Aventis Pharma S.A. Benzoxazine derivatives and their therapeutic use
FR2796943A1 (en) * 1999-07-30 2001-02-02 Aventis Pharma Sa BENZOXAZINN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USE IN THERAPEUTICS
EP1088821A1 (en) * 1999-09-28 2001-04-04 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives
JP2003510319A (en) * 1999-09-28 2003-03-18 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ Pharmaceutically active sulfonamide derivatives
JP5015397B2 (en) * 1999-09-28 2012-08-29 メルク セローノ ソシエテ アノニム Pharmaceutically active sulfonamide derivatives
EA005368B1 (en) * 1999-09-28 2005-02-24 Апплайд Резеч Системз Арс Холдинг Н.В. Pharmaceutically active sulfonamide derivatives
US8012995B1 (en) 1999-09-28 2011-09-06 Merck Serono Sa Pharmaceutically active sulfonamide derivatives
WO2001023378A1 (en) * 1999-09-28 2001-04-05 Applied Research Systems Ars Holding N.V. Pharmaceutically active sulfonamide derivatives
KR100827533B1 (en) * 1999-09-28 2008-05-06 라보라토리스 세로노 에스.에이. Pharmaceutically active sulfonamide derivatives
US6100395A (en) * 2000-01-10 2000-08-08 Bristol-Myers Squibb Company Reductive alkylation of secondary amines with hydrosilane
US6838467B2 (en) 2000-02-24 2005-01-04 Janssen Pharmaceutica N. V. Dosing regimen
EP1283055A1 (en) * 2000-04-07 2003-02-12 Takeda Chemical Industries, Ltd. Soluble beta amyloid precursor protein secretion promoters
EP1283055A4 (en) * 2000-04-07 2003-05-07 Takeda Chemical Industries Ltd Soluble beta amyloid precursor protein secretion promoters
WO2001081322A1 (en) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
US6645966B2 (en) 2001-01-22 2003-11-11 Schering Corporation Treatment of malaria with farnesyl protein transferase inhibitors
EP1938821A2 (en) 2001-01-25 2008-07-02 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
US7759323B2 (en) 2001-05-22 2010-07-20 Eisai R & D Management Co., Ltd. Highly purified antiendotoxin compound
US8377893B2 (en) 2001-05-22 2013-02-19 Eisai R&D Management Co., Ltd. Highly purified antiendotoxin compound
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US9181188B2 (en) 2002-02-11 2015-11-10 Bayer Healthcare Llc Aryl ureas as kinase inhibitors
US7405234B2 (en) 2002-05-17 2008-07-29 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
US7772267B2 (en) 2002-05-17 2010-08-10 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
GB2405146A (en) * 2002-06-07 2005-02-23 Cortical Pty Ltd Napthalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (MIF)
WO2003104178A1 (en) * 2002-06-07 2003-12-18 Cortical Pty Ltd Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
US7632858B2 (en) 2002-11-15 2009-12-15 Bristol-Myers Squibb Company Open chain prolyl urea-related modulators of androgen receptor function
EP1591120A4 (en) * 2003-01-28 2009-06-10 Takeda Chemical Industries Ltd Receptor agonists
US7625887B2 (en) 2003-01-28 2009-12-01 Takeda Pharmaceutical Company Limited Receptor agonists
EP1591120A1 (en) * 2003-01-28 2005-11-02 Takeda Chemical Industries, Ltd. Receptor agonists
WO2004085388A2 (en) 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8674075B2 (en) 2003-08-13 2014-03-18 Children's Medical Center Corporation Chimeric peptides for the regulation of GTPases
US9353166B2 (en) 2003-08-13 2016-05-31 Children's Medical Center Corporation Chimeric peptides for the regulation of GTPases
US7915384B2 (en) 2003-08-13 2011-03-29 Children's Hospital Medical Center Chimeric peptides for the regulation of GTPases
US8242246B2 (en) 2003-08-13 2012-08-14 Children's Hospital Medical Center Chimeric peptides for the regulation of GTPases
US7417026B2 (en) 2003-08-13 2008-08-26 Children's Hospital Medical Center Mobilization of hematopoietic cells
US7820702B2 (en) 2004-02-04 2010-10-26 Bristol-Myers Squibb Company Sulfonylpyrrolidine modulators of androgen receptor function and method
US7989640B2 (en) 2004-02-04 2011-08-02 Bristol-Myers Squibb Company Sulfonylpyrrolidine modulators of androgen receptor function and method
WO2005084295A2 (en) 2004-03-01 2005-09-15 Bristol-Myers Squibb Company Fused heterotricyclic compounds as inhibitors of 17b-hydroxysteroid dehydrogenase 3
WO2005087232A1 (en) 2004-03-04 2005-09-22 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
US7732480B2 (en) 2004-03-04 2010-06-08 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
US7696241B2 (en) 2004-03-04 2010-04-13 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
US7625923B2 (en) 2004-03-04 2009-12-01 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
EP1742640A2 (en) * 2004-04-27 2007-01-17 The Regents of The University of Michigan Technology Management Wolverine Tower Office Methods and compositions for treating diseases and conditions associated with mitochondrial function
AU2005323519B2 (en) * 2004-04-27 2009-09-10 The Regents Of The University Of Michigan Methods and compositions for treating diseases and conditions associated with mitochondrial function
EP1742640A4 (en) * 2004-04-27 2008-12-24 Univ Michigan Technology Man W Methods and compositions for treating diseases and conditions associated with mitochondrial function
US10675326B2 (en) 2004-10-07 2020-06-09 The Board Of Trustees Of The University Of Illinois Compositions comprising cupredoxins for treating cancer
EP2362218A3 (en) * 2004-11-05 2011-10-26 Janssen Pharmaceutica N.V. Methods of monitoring the efficacy of farnesyltransferase inhibitors
EP2362218A2 (en) 2004-11-05 2011-08-31 Janssen Pharmaceutica N.V. Methods of monitoring the efficacy of farnesyltransferase inhibitors
WO2006052718A3 (en) * 2004-11-05 2007-06-28 Janssen Pharmaceutica Nv Farnesyltransferase inhibitors for treating sepsis
EP1958625A1 (en) 2004-11-18 2008-08-20 Brystol-Myers Squibb Company Enteric coate bead comprising ixabepilone and preparation thereof
WO2006104008A1 (en) * 2005-03-25 2006-10-05 Kissei Pharmaceutical Co., Ltd. Urea derivative, medicinal composition containing the same, and medicinal use of these
JP5009785B2 (en) * 2005-03-25 2012-08-22 キッセイ薬品工業株式会社 Urea derivatives, pharmaceutical compositions containing them and their pharmaceutical use
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
WO2007024949A3 (en) * 2005-08-25 2007-06-07 Schering Corp Alpha2c adrenoreceptor agonists
US7700592B2 (en) 2005-08-25 2010-04-20 Schering Corporation α2C adrenoreceptor agonists
US7985748B2 (en) 2005-08-25 2011-07-26 Pharmacopeia Drug Discovery, Inc. ALPHA2C adrenoreceptor agonists
US7687499B2 (en) 2005-09-16 2010-03-30 Janssen Pharmaceutica Nv Cyclopropyl amines as modulators of the histamine H3 receptor
US8026242B2 (en) 2005-09-16 2011-09-27 Carruthers Nicholas I Cyclopropyl amines as modulators of the histamine H3 receptor
US7910582B2 (en) 2005-09-16 2011-03-22 Janssen Pharmaceutica Nv Cyclopropyl amines as modulators of the histamine H3 receptor
US9266866B2 (en) 2006-04-20 2016-02-23 Janssen Pharmaceutica Nv Inhibitors of C-FMS kinase
US8759347B2 (en) 2006-04-20 2014-06-24 Janssen Pharmaceutica Nv Inhibitors of C-FMS kinase
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US8895584B2 (en) 2006-04-20 2014-11-25 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US8933091B2 (en) 2006-04-20 2015-01-13 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US9296726B2 (en) 2006-04-20 2016-03-29 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US9526731B2 (en) 2006-04-20 2016-12-27 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US9394289B2 (en) 2006-04-20 2016-07-19 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9403804B2 (en) 2006-04-20 2016-08-02 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US11046733B2 (en) 2006-12-04 2021-06-29 The Board Of Trustees Of The University Of Illinois Compositions and methods to treat cancer with CpG rich DNA and cupredoxins
US9969781B2 (en) 2006-12-04 2018-05-15 Tapas Das Gupta Compositions and methods to treat cancer with CpG rich DNA and cupredoxins
US8017749B2 (en) 2006-12-04 2011-09-13 The Board Of Trustees Of The University Of Illinois Compositions and methods to treat cancer with cupredoxins and CpG rich DNA
US7893257B2 (en) 2006-12-14 2011-02-22 Janssen Pharmaceutica Nv Process for the preparation of piperazinyl and diazepanyl benzamide derivatives
US8680273B2 (en) 2006-12-14 2014-03-25 Janssen Pharmaceutica Nv Process for the preparation of piperazinyl and diazepanyl benzamide derivatives
US10086037B2 (en) 2007-02-08 2018-10-02 Tapas Das Gupta Compositions and methods to prevent cancer with cupredoxins
US8232244B2 (en) 2007-02-08 2012-07-31 The Board Of Trustees Of The University Of Illinois Compositions and methods to prevent cancer with cupredoxins
WO2008100463A1 (en) 2007-02-13 2008-08-21 Schering Corporation 3,4-dihydr0-l,4-benz0xazine, 3, 4-dihydr0-1, 4-benzothiazine and 1,2,3,4-tetrahydro-quinoxaline derivatives as alpha2c adrenoreceptor agonists
EP2163538A1 (en) * 2007-05-25 2010-03-17 Topharman Shanghai Co., Ltd. Preparation methods of 4-acetyl-2,3,4,5-tetrahydro- benzo[1,4]diazepine and their intermediates
EP2163538A4 (en) * 2007-05-25 2010-11-24 Topharman Shanghai Co Ltd Preparation methods of 4-acetyl-2,3,4,5-tetrahydro- benzo[1,4]diazepine and their intermediates
WO2008153858A1 (en) 2007-06-05 2008-12-18 Schering Corporation Polycyclic indazole derivatives and their use as erk inhibitors for the treatment of cancer
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
WO2011041152A1 (en) 2009-09-30 2011-04-07 Schering Corporation Novel compounds that are erk inhibitors
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
US9849138B2 (en) 2009-11-17 2017-12-26 The Regents Of The University Of Michigan 1,4-benzodiazepone-2,5-diones and related compounds with therapeutic properties
WO2011163330A1 (en) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Novel heterocyclic compounds as erk inhibitors
WO2012030685A2 (en) 2010-09-01 2012-03-08 Schering Corporation Indazole derivatives useful as erk inhibitors
WO2012087772A1 (en) 2010-12-21 2012-06-28 Schering Corporation Indazole derivatives useful as erk inhibitors
WO2012100206A2 (en) 2011-01-20 2012-07-26 Board Of Regents, The University Of Texas System Mri markers, delivery and extraction systems, and methods of manufacture and use thereof
US9138421B2 (en) 2011-07-09 2015-09-22 Beijing Fswelcome Technology Development Co., Ltd. Platinum compounds for treating cell proliferative diseases, preparation method and use thereof
WO2013007172A1 (en) 2011-07-09 2013-01-17 北京市丰硕维康技术开发有限责任公司 Platinum compounds for treating cell proliferative disease, preparation methods and uses thereof
WO2013041014A1 (en) 2011-09-19 2013-03-28 北京市丰硕维康技术开发有限责任公司 Platinum compound having amino- or alkylamino-containing succinic acid derivatives as leaving group, preparation method therefor, and use thereof
US9175024B2 (en) 2011-09-19 2015-11-03 Beijing Fswelcome Technology Development Co., Ltd. Platinum compound having amino or alkylamino-containing succinic acid derivatives as leaving group, preparation method thereof, and use thereof
WO2013064231A1 (en) 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3)
US9951153B2 (en) 2012-07-31 2018-04-24 Dow Global Technologies Llc Method of making an olefin polymerization catalyst activator
US10730964B2 (en) 2012-07-31 2020-08-04 Dow GlobalTechnologies LLC Method of making an olefin polymerization catalyst activator
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors
WO2014075391A1 (en) 2012-11-17 2014-05-22 北京市丰硕维康技术开发有限责任公司 Platinum compound of malonic acid derivative having leaving group containing amino or alkylamino
US9725477B2 (en) 2012-11-17 2017-08-08 Beijing Fswelcome Technology Development Co., Ltd Platinum compounds of malonic acid derivative having leaving group containing amino or alkylamino
US10919850B2 (en) 2013-03-15 2021-02-16 Araxes Pharma Llc Covalent inhibitors of KRas G12C
EP3401314A1 (en) * 2013-03-15 2018-11-14 Araxes Pharma LLC Covalent inhibitors of kras g12c
US10273207B2 (en) 2013-03-15 2019-04-30 Araxes Pharma Llc Covalent inhibitors of kras G12C
US11878985B2 (en) 2013-10-10 2024-01-23 Araxes Pharma Llc Substituted quinazolines as inhibitors of KRAS G12C
US10927125B2 (en) 2013-10-10 2021-02-23 Araxes Pharma Llc Substituted cinnolines as inhibitors of KRAS G12C
US10370386B2 (en) 2013-10-10 2019-08-06 Araxes Pharma Llc Substituted quinolines as inhibitors of KRAS G12C
WO2015200920A1 (en) 2014-06-27 2015-12-30 The Regents Of The University Of California Cultured mammalian limbal stem cells, methods for generating the same, and uses thereof
US10829458B2 (en) 2015-04-10 2020-11-10 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10428064B2 (en) 2015-04-15 2019-10-01 Araxes Pharma Llc Fused-tricyclic inhibitors of KRAS and methods of use thereof
US10351550B2 (en) 2015-07-22 2019-07-16 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10292979B2 (en) 2015-08-17 2019-05-21 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
EP3640345A1 (en) 2015-08-17 2020-04-22 Kura Oncology, Inc. Methods of treating cancer patients with farnesyl transferase inhibitors
US10335404B2 (en) 2015-08-17 2019-07-02 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US9707221B2 (en) 2015-08-17 2017-07-18 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
WO2017031101A1 (en) 2015-08-17 2017-02-23 Kura Oncology, Inc. Methods of treating cancer patients with farnesyl transferase inhibitors
EP3995589A1 (en) 2015-08-17 2022-05-11 Kura Oncology, Inc. Methods of treating cancer patients with farnesyl transferase inhibitors
EP3385395A1 (en) 2015-08-17 2018-10-10 Kura Oncology, Inc. Methods of treating cancer patients with farnesyl transferase inhibitors
US11207314B2 (en) 2015-08-17 2021-12-28 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US10022364B2 (en) 2015-08-17 2018-07-17 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US10471055B2 (en) 2015-08-17 2019-11-12 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10882847B2 (en) 2015-09-28 2021-01-05 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10875842B2 (en) 2015-09-28 2020-12-29 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10647703B2 (en) 2015-09-28 2020-05-12 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10689356B2 (en) 2015-09-28 2020-06-23 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10858343B2 (en) 2015-09-28 2020-12-08 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10730867B2 (en) 2015-09-28 2020-08-04 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US11021470B2 (en) 2015-11-16 2021-06-01 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
WO2017184968A1 (en) 2016-04-22 2017-10-26 Kura Oncology, Inc. Methods of selecting cancer patients for treatment with farnesyltransferase inhibitors
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10723738B2 (en) 2016-09-29 2020-07-28 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10377743B2 (en) 2016-10-07 2019-08-13 Araxes Pharma Llc Inhibitors of RAS and methods of use thereof
US11124839B2 (en) 2016-11-03 2021-09-21 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
EP3838275A1 (en) 2016-11-03 2021-06-23 Kura Oncology, Inc. Farnesyltransferase inhibitors for use in methods of treating cancer
WO2018085518A2 (en) 2016-11-03 2018-05-11 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
US11136308B2 (en) 2017-01-26 2021-10-05 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11541045B2 (en) 2017-02-21 2023-01-03 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10426767B2 (en) 2017-02-21 2019-10-01 Kura Oncolofy, Inc. Methods of treating cancer with farnesyltransferase inhibitors
EP3542800A1 (en) 2017-02-21 2019-09-25 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
EP4119142A1 (en) 2017-02-21 2023-01-18 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10980793B2 (en) 2017-02-21 2021-04-20 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2018156609A1 (en) 2017-02-21 2018-08-30 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10137121B2 (en) 2017-02-21 2018-11-27 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US9956215B1 (en) 2017-02-21 2018-05-01 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10736897B2 (en) 2017-05-25 2020-08-11 Araxes Pharma Llc Compounds and methods of use thereof for treatment of cancer
US11377441B2 (en) 2017-05-25 2022-07-05 Araxes Pharma Llc Covalent inhibitors of KRAS
US11639346B2 (en) 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS
US10745385B2 (en) 2017-05-25 2020-08-18 Araxes Pharma Llc Covalent inhibitors of KRAS
US11291663B2 (en) 2017-08-07 2022-04-05 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
US10806730B2 (en) 2017-08-07 2020-10-20 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2019113269A1 (en) 2017-12-08 2019-06-13 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
WO2020084580A1 (en) 2018-10-26 2020-04-30 Novartis Ag Methods and compositions for ocular cell therapy
WO2020092720A2 (en) 2018-11-01 2020-05-07 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020132437A1 (en) 2018-12-21 2020-06-25 Kura Oncology, Inc. Therapies for squamous cell carcinomas
WO2020180663A1 (en) 2019-03-01 2020-09-10 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020190604A1 (en) 2019-03-15 2020-09-24 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
WO2020205486A1 (en) 2019-03-29 2020-10-08 Kura Oncology, Inc. Methods of treating squamous cell carcinomas with farnesyltransferase inhibitors
WO2020205387A1 (en) 2019-04-01 2020-10-08 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020223583A1 (en) 2019-05-02 2020-11-05 Kura Oncology, Inc. Methods of treating acute myeloid leukemia with farnesyltransferase inhibitors
WO2020236940A1 (en) * 2019-05-20 2020-11-26 California Institute Of Technology Kras g12c inhibitors and uses thereof
WO2021220132A1 (en) 2020-04-27 2021-11-04 Novartis Ag Methods and compositions for ocular cell therapy
WO2023143389A1 (en) * 2022-01-29 2023-08-03 江苏恒瑞医药股份有限公司 Fused heterocyclic compound, preparation method therefor, and medical application thereof

Also Published As

Publication number Publication date
KR100522983B1 (en) 2006-09-20
IL141908A0 (en) 2002-03-10
US6011029A (en) 2000-01-04
PL191502B1 (en) 2006-05-31
CA2239187C (en) 2003-04-22
HUP9902016A3 (en) 2000-02-28
CN1347881A (en) 2002-05-08
PL328868A1 (en) 1999-03-01
SK286568B6 (en) 2009-01-07
HUP9902016A2 (en) 1999-09-28
CN1214685A (en) 1999-04-21
AU2136697A (en) 1997-09-10
LV12150A (en) 1998-10-20
LV12150B (en) 1998-12-20
RO121118B1 (en) 2006-12-29
BR9707614A (en) 1999-07-27
EE04309B1 (en) 2004-06-15
JP4115529B2 (en) 2008-07-09
KR19990087250A (en) 1999-12-15
NO983892L (en) 1998-08-25
IL141908A (en) 2003-04-10
BG102738A (en) 1999-09-30
BG64951B1 (en) 2006-10-31
GEP20022616B (en) 2002-01-25
NZ330287A (en) 2000-03-27
JP2000502356A (en) 2000-02-29
AU718676B2 (en) 2000-04-20
EP0892797A1 (en) 1999-01-27
SK117398A3 (en) 2000-12-11
NO319395B1 (en) 2005-08-08
US6455523B1 (en) 2002-09-24
CZ299762B6 (en) 2008-11-12
EE9800262A (en) 1999-02-15
CA2239187A1 (en) 1997-08-28
EP0892797A4 (en) 2004-10-20
TW496863B (en) 2002-08-01
CZ269698A3 (en) 1999-10-13
IL124197A (en) 2003-06-24
EP1481975A1 (en) 2004-12-01
NO983892D0 (en) 1998-08-25
UA52642C2 (en) 2003-01-15
RU2225405C2 (en) 2004-03-10
CN100376569C (en) 2008-03-26

Similar Documents

Publication Publication Date Title
US6455523B1 (en) Inhibitors of farnesyl protein transferase
AU735366B2 (en) Inhibitors of farnesyl protein transferase
US6387926B1 (en) Inhibitors of farnesyl protein transferase
JP6680683B2 (en) Tetrahydro-benzodiazepinones
EP0918771A1 (en) Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase
TW200808781A (en) Substituted piperidines that increase P53 activity and the uses thereof
US6458783B1 (en) Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
LT4552B (en) Inhibitors of farnesyl protein transferase

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 97192535.6

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 330287

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2239187

Country of ref document: CA

Ref document number: 2239187

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 1998 980129

Country of ref document: LV

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1998980129

Country of ref document: LV

ENP Entry into the national phase

Ref document number: 1997 530395

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV1998-2696

Country of ref document: CZ

Ref document number: 98-01326

Country of ref document: RO

WWE Wipo information: entry into national phase

Ref document number: 98120

Country of ref document: LT

Ref document number: 1019980706651

Country of ref document: KR

Ref document number: 98-120

Country of ref document: LT

Ref document number: PA/A/1998/006887

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 117398

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 1997906761

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1997906761

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 98-120

Country of ref document: LT

WWP Wipo information: published in national office

Ref document number: PV1998-2696

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 98-120

Country of ref document: LT

WWP Wipo information: published in national office

Ref document number: 1019980706651

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 141908

Country of ref document: IL

WWR Wipo information: refused in national office

Ref document number: 1019980706651

Country of ref document: KR